Quinazolinone compounds with reduced bioaccumulation

ABSTRACT

A variety of small molecule, guanidine-containing molecules capable of acting as MC4-R agonists are provided. The compounds are useful in treating MC4-R mediated diseases when administered to subjects. The compounds have the formula IA and IB. IA and IB have the following structures where Z has the formula shown below and the rest of the variables are defined herein

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/523,336 filed Nov. 19, 2003, and U.S. Provisional Application No.60/524,492 filed Nov. 24, 2003, the entire disclosures of which areincorporated herein by reference and for all purposes as if fully setforth herein.

FIELD OF THE INVENTION

This invention relates to melanocortin-4 receptor (MC4-R) agonists andmethods of their preparation. More specifically, the invention relatesto quinazolinone compounds that exhibit reduced bioaccumulationproperties when administered to a subject.

BACKGROUND OF THE INVENTION

Melanocortins are peptide products resulting from post-translationalprocessing of pro-opiomelanocortin and are known to have a broad arrayof physiological activities. The natural melanocortins include thedifferent types of melanocyte stimulating hormone (α-MSH, β-MSH, γ-MSH)and ACTH. Of these, α-MSH and ACTH are considered to be the mainendogenous melanocortins.

The melanocortins mediate their effects through melanocortin receptors(MC-Rs), a subfamily of G-protein coupled receptors. There are at leastfive different receptor subtypes (MC1-R to MC5-R). MC1-R mediatespigmentation of the hair and skin. MC2-R mediates the effects of ACTH onsteroidogenesis in the adrenal gland. MC3-R and MC4-R are predominantlyexpressed in the brain. MC5-R is considered to have a role in theexocrine gland system.

The melanocortin-4 receptor (MC4-R) is a seven-transmembrane receptor.MC4-R may participate in modulating the flow of visual and sensoryinformation, coordinate aspects of somatomotor control, and/orparticipate in the modulation of autonomic outflow to the heart. K. G.Mountjoy et al., Science, 257: 1248-125 (1992). Significantly,inactivation of this receptor by gene targeting has resulted in micethat develop a maturity onset obesity syndrome associated withhyperphagia, hyperinsulinemia, and hyperglycemia. D. Husznar et al.,Cell, 88(1): 131-41 (1997). MC4-R has also been implicated in otherdisease states including erectile disorders, cardiovascular disorders,neuronal injuries or disorders, inflammation, fever, cognitivedisorders, and sexual behavior disorders. M. E. Hadley and C.Haskell-Luevano, The proopiomelanocortin system, Ann. N.Y. Acad. Sci.,885: 1 (1999).

Furthermore, observations in connection with endogenous MC4-Rantagonists indicate that MC4-R is implicated in endogenous energyregulation. For example, an agouti protein is normally expressed in theskin and is an antagonist of the cutaneous MC receptor involved inpigmentation, MC1-R. M. M. Ollmann et al., Science, 278: 135-138 (1997).However, overexpression of agouti protein in mice leads to a yellow coatcolor due to antagonism of MC1-R and increased food intake and bodyweight due to antagonism of MC4-R. L. L. Kiefer et al., Biochemistry,36: 2084-2090 (1997); D. S. Lu et al., Nature, 371: 799-802 (1994).Agouti related protein (AGRP), an agouti protein homologue, antagonizesMC4-R but not MC1-R. T. M. Fong et al., Biochem. Biophys. Res. Commun.237: 629-631 (1997). Administration of AGRP in mice increases foodintake and causes obesity but does not alter pigmentation. M. Rossi etal., Endocrinology, 139: 4428-4431 (1998). Together, this researchindicates that MC4-R participates in energy regulation, and therefore,identifies this receptor as a target for a rational drug design for thetreatment of obesity.

In connection with MC4-R and its uncovered role in the etiology ofobesity and food intake, the prior art includes reports of compounds andcompositions that act as agonists or antagonists of MC4-R. As examples,U.S. Pat. No. 6,060,589 describes polypeptides that are capable ofmodulating signaling activity of melanocortin receptors. Also, U.S. Pat.Nos. 6,054,556 and 5,731,408 describe families of agonists andantagonists for MC4-R receptors that are lactam heptapeptides having acyclic structure. WO 01/10842 discloses MC4-R binding compounds having amultitude of structures and methods of using such compounds to treatMC4-R associated disorders. Some of the compounds described includeamidino- and guanidino-containing arenes and heteroarenes.

Various other classes of compounds have been disclosed as having MC4-Ragonist activity. For example, WO 01/70708 and WO 00/74679 discloseMC4-R agonists that are piperidine compounds and derivatives, while WO01/70337 and WO 99/64002 disclose MC-R agonists that are spiropiperidinederivatives. Other known melanocortin receptor agonists include aromaticamine compounds containing amino acid residues, particularly tryptophanresidues, as disclosed in WO 01/55106. Similar agonists are disclosed inWO 01/055107 which comprise aromatic amine compounds containing tertiaryamide or tertiary amine groups. Finally, WO 01/055109 disclosesmelanocortin receptor agonists comprising aromatic amines which aregenerally bisamides separated by a nitrogen-containing alkyl linker.

Guanidine-containing compounds having a variety of biological activitiesare also known in the prior art. For example, U.S. Pat. No. 4,732,916issued to Satoh et al. discloses guanidine compounds useful as antiulceragents; U.S. Pat. No. 4,874,864, U.S. Pat. No. 4,949,891, and U.S. Pat.No. 4,948,901 issued to Schnur et al. and EP 0343 894 disclose guanidinocompounds useful as protease inhibitors and as anti-plasmin andanti-thrombin agents; and U.S. Pat. No. 5,352,704 issued to Okuyama etal. discloses a guanidino compound useful as an antiviral agent.Guanidine-containing compounds are also disclosed in other references.For example, U.S. Pat. No. 6,030,985 issued to Gentile et al. disclosesguanidine compounds useful for treating and preventing conditions inwhich inhibition of nitric oxide synthetase is beneficial such asstroke, schizophrenia, anxiety, and pain. U.S. Pat. No. 5,952,381 issuedto Chen et al. discloses certain guanidine compounds for use inselectively inhibiting or antagonizing α_(v)β₃ integrins.

Various 5-, 6-, and 7-membered fully saturated1-azacarbocyclic-2-ylidene derivatives of guanidine are disclosed ashaving anti-secretory and hypoglycemic activities by U.S. Pat. No.4,211,867 issued to Rasmussen. Such compounds are also taught as usefulfor the treatment of cardiovascular disease. Other guanidine derivativesare disclosed by U.S. Pat. No. 5,885,985 issued to Macdonald et al. asuseful in therapy to treat inflammation. Various guanidinobenzamidecompounds are disclosed in WO 02/18327. The guanidinobenzamides aredisclosed as useful for treating obesity and type II diabetes.

The synthesis of various quinazolinone compounds is set forth in U.S.patent application Ser. No. 10/444,495, published on Jan. 29, 2004 asU.S. 2004/0019049, international application number PCT/US03/16442,published on Dec. 4, 2003 as WO 03/099818, U.S. patent application Ser.No. 10/850,967, filed on May 21, 2004; international application no.PCT/US04/15959; and U.S. Provisional Application Nos. 60/382,762,60/441,019, 60/473,317, 60/523,336, and 60/524,492 each of which ishereby incorporated by reference in its entirety and for all purposes asif fully set forth herein.

Despite the recent disclosure of various compounds that exhibit MC4-Ragonist activity, a need remains for new compounds and pharmaceuticalcompositions that may be used to treat MC4-R mediated diseases anddisease states. A need also remains for compounds that exhibit desirablepharmacological properties such as compounds that have reducedbioaccumulation properties in subjects to which they are administered.

SUMMARY OF THE INVENTION

The instant invention provides potent and specific agonists of MC4-Rthat are small molecules. Thus, there has been provided, in accordancewith one aspect of the invention, compounds of formula IA, IB, mixturesthereof, or pharmaceutically acceptable salts thereof

where

-   -   R¹ is selected from substituted or unsubstituted arylalkyl,        heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,        heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl        groups;    -   R² is selected from H or substituted or unsubstituted arylalkyl,        heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl,        heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl,        cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups;    -   R³, R⁴, and R⁵ are independently selected from H, Cl, I, F, Br,        OH, NH₂, CN, NO₂, or substituted or unsubstituted alkoxy or        alkyl groups;    -   R^(3′) is selected from H or substituted or unsubstituted aryl,        alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl,        heterocyclylalkyl, arylalkyl, heteroarylalkyl, or        cycloalkylalkyl groups; and    -   Z is selected from a piperazinone of formula        which may be additionally substituted.

Compounds provided by the invention further include prodrugs of thecompounds of formula IA and IB, pharmaceutically acceptable saltsthereof, stereoisomers thereof, tautomers thereof, hydrates thereof, orsolvates thereof.

The invention further provides compounds of formula IA and IB in whichR³, R⁴, and R⁵ are all H.

The invention further provides compounds of formula IA and IB in whichR^(3′) is selected from the group consisting of substituted andunsubstituted cyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl,trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl,cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and decalinyl groups.In still other embodiments, R^(3′) is selected from the group consistingof substituted and unsubstituted cyclohexyl, 2-methylcyclohexyl,2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl,2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl,3-methylcyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl,4-t-butylcyclohexyl, isopinocampheyl, 7,7-dimethylnorbornyl,4-isopropylcyclohexyl, 3-methylcycloheptyl groups,2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl,4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethylcyclohexyl,2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl,trifluoromethyl(polycyclic cycloalkyl), fluoromethyl(polycycliccycloalkyl), and fluoro(polycyclic cycloalkyl) groups.

The invention further provides compounds of formula IA and IB in whichR^(3′) is a substituted or unsubstituted polycyclic cycloalkyl group. Insome such embodiments, R^(3′) is a substituted or unsubstitutedpolycyclic cycloalkyl group having the formula II

The invention further provides compounds of formula IA and IB in whichR¹ is a substituted or unsubstituted arylalkyl group such as asubstituted or unsubstituted phenylethyl group. In some suchembodiments, R¹ is a substituted phenylethyl group such as a4-substituted phenylethyl group or a 2,4-disubstituted phenylethylgroup. In some embodiments, R¹ is selected from phenylethyl,2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl,4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl,4-fluorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl,2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl,3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl,4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl,2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl,4-chloro-2-fluorophenylethyl, 4-bromo-2-fluorophenylethyl,2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl,2,4-difluorophenylethyl, 2,4-dimethylphenylethyl,2,4-dimethoxyphenylethyl, (2-pyridyl)ethyl, (3-pyridyl)ethyl,(4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, and(phenyl)(hydroxymethyl)ethyl groups. In still other embodiments, R¹ isselected from 2-fluoro-4-methoxyphenylethyl,2-chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, 4-chlorophenylethyl,4-chloro-2-fluorophenylethyl, 2,4-dichlorophenylethyl,4-bromophenylethyl, or 4-bromo-2-fluorophenylethyl groups.

The invention further provides compounds of formula IA and IB in whichR² is selected from substituted or unsubstituted heterocyclyl groups orsubstituted or unsubstituted heteroaryl groups. In some embodiments, R²is selected from substituted or unsubstituted pyridinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl,pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl,pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl, tetrazolyl,or pyridazinyl groups. In some such embodiments, R² is selected fromheteroaryl or heterocyclyl groups of formula

which may be additionally substituted or may be unsubstituted.

The invention further provides compounds of formula IA and IB in whichR² is selected from substituted or unsubstituted aryl or cycloalkylgroups. For example, in some embodiments, R² is selected from aryl orcycloalkyl groups of formula

which may be additionally substituted or may be unsubstituted.

The invention further provides compounds of formula IA and IB in whichR² is selected from substituted or unsubstituted heterocyclylalkyl, orcycloalkylamino groups. For example, in some embodiments, R² is selectedfrom a group such as a substituted or unsubstituted cyclopropylaminogroup; a substituted or unsubstituted piperazinylalkyl group such as apiperazinylmethyl group or an N-methylpiperazinylmethyl group; or apiperidinylalkyl group such as a piperidinylmethyl group or apiperidinylethyl group.

The invention further provides compounds of formula IA and IB in which Zis a piperazinone having the following formula

In some such embodiments, Z is a piperazinone having the followingformula

In some embodiments, the invention provides compounds in which thet_(1/2) value for the compound is less than 35, 30, 25, 20, 15, 10, or 5hours in a tissue with high blood perfusion such as brain, liver,kidney, and heart. In some such embodiments, the t_(1/2) is less than orabout 4 hours and in some embodiments is less than or about 3 hours in asubject to which the compound(s) have been administered.

There has also been provided, in accordance with another aspect of theinvention, a composition such as a pharmaceutical formulation ormedicament comprising a compound according to the instant invention anda pharmaceutically acceptable carrier. The invention further providesthe use of the compounds of the invention in preparing a medicament orpharmaceutical formulation for use in treating an MC4-R mediateddisease. In some embodiments, such a disease is obesity or type IIdiabetes.

There has also been provided, in accordance with another aspect of theinvention, a method of treating an MC4-R mediated disease, comprisingadministering to a subject in need thereof, a compound or composition ofthe instant invention. In some such embodiments, the compounds of theinvention exhibit reduced bioaccumulation in the tissue and plasma ofthe subject.

In one embodiment, a disease to be treated by those methods of theinstant invention is obesity or type II diabetes.

In one embodiment, a compound or composition of the invention isintranasally administered.

In one embodiment, a compound or composition of the invention isadministered to a human subject.

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION

The instant invention relates to novel classes of small moleculemelanocortin-4 receptor (MC4-R) agonists. These compounds can beformulated into compositions and are useful in activating MC4-R, or inthe treatment of MC4-R-mediated diseases, such as obesity, type IIdiabetes, erectile dysfunction, polycystic ovary disease, complicationsresulting from or associated with obesity and diabetes, and Syndrome X.

The following definitions are used throughout this specification.

Alkyl groups include straight chain and branched alkyl groups havingfrom 1 to about 8 carbon atoms. Examples of straight chain alkyl groupsinclude methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octylgroups. Examples of branched alkyl groups, include, but are not limitedto, isopropyl, sec-butyl, t-butyl, and isopentyl groups. Representativesubstituted alkyl groups may be substituted one or more times with, forexample, amino, thio, alkoxy, or halo groups such as F, Cl, Br, and Igroups.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl groups. Cycloalkyl groups also includes rings that aresubstituted with straight or branched chain alkyl groups as definedabove, and further include cycloalkyl groups that are substituted withother rings including fused rings such as, but not limited to,decalinyl, tetrahydronaphthyl, and indanyl. Cycloalkyl groups alsoinclude polycyclic cycloalkyl groups such as, but not limited to,norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenylgroups. Representative substituted cycloalkyl groups may bemono-substituted or substituted more than once, such as, but not limitedto, 2,2-, 2,3-, 2,4-2,5- or 2,6-disubstituted cyclohexyl groups ormono-, di- or tri-substituted norbornyl or cycloheptyl groups, which maybe substituted with, for example, alkyl, alkoxy, amino, thio, cyano, orhalo groups.

Alkenyl groups are straight chain, branched or cyclic lower alkyl groupshaving 2 to about 8 carbon atoms, and further including at least onedouble bond, as exemplified, for instance, by vinyl, propenyl,2-butenyl, 3-butenyl, isobutenyl, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl groups amongothers.

Alkynyl groups are straight chain or branched lower alkyl groups having2 to about 8 carbon atoms, and further including at least one triplebond, as exemplified by groups, including, but not limited to, ethynyl,propynyl, and butynyl groups.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulene, heptalene, biphenylene, indacene, fluorene, phenanthrene,triphenylene, pyrene, naphthacene, chrysene, biphenyl, anthracenyl, andnaphthenyl groups. Although the phrase “aryl groups” includes groupscontaining fused rings, such as fused aromatic-aliphatic ring systems,it does not include aryl groups that have other groups, such as alkyl orhalo groups, bonded to one of the ring members. Rather, groups such astolyl are referred to as substituted aryl groups. Representativesubstituted aryl groups may be mono-substituted or substituted more thanonce, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substitutedphenyl or benzyl groups, which may be substituted with groups including,but not limited to, amino, alkoxy, alkyl, cyano, or halo. In someembodiments, aryl groups have from 6 to 14 ring member carbon atoms.

Cycloalkylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to acycloalkyl group as defined above.

Arylalkyl groups are alkyl groups as defined above in which a hydrogenor carbon bond of an alkyl group is replaced with a bond to an arylgroup as defined above.

Heterocyclyl groups are nonaromatic ring compounds containing 3 or morering members, of which, one or more is a heteroatom such as, but notlimited to, N, O, and S. The phrase “heterocyclyl group” includes fusedring species including those comprising fused aromatic and nonaromaticgroups. The phrase also includes polycyclic ring systems containing aheteroatom such as, but not limited to, quinuclidyl. However, the phrasedoes not include heterocyclyl groups that have other groups, such asalkyl or halo groups, bonded to one of the ring members. Rather, theseare referred to as “substituted heterocyclyl groups”. Heterocyclylgroups include, but are not limited to, piperazino, morpholino,thiomorpholino, pyrrolidino, piperidino and homopiperazino groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, morpholinoor piperazino groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with groups including, but not limited to, amino, alkoxy,alkyl, cyano, or halo.

Heteroaryl groups are aromatic ring compounds containing 3 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups include, but are not limited to,groups such as furan, thiophene, pyrrole, isopyrrole, diazole,imidazole, isoimidazole, triazole, dithiole, oxathiole, isoxazole,oxazole, thiazole, isothiazole, oxadiazole, oxatriazole, dioxazole,oxathiazole, pyran, dioxin, pyridine, pyrimidine, pyridazine, pyrazine,triazine, oxazine, isoxazine, oxathiazine, azepin, oxepin, thiepin,diazepine, benzofuran, and isobenzofuran. Although the phrase“heteroaryl groups” includes fused ring compounds, the phrase does notinclude heteroaryl groups that have other groups bonded to one of thering members, such as alkyl groups. Rather, heteroaryl groups with suchsubstitution are referred to as “substituted heteroaryl groups”.Representative substituted heteroaryl groups may be substituted one ormore times with groups including, but not limited to, amino, alkoxy,alkyl, cyano, or halo. In some embodiments, heteroaryl groups includefrom 5 to 14 ring members.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above.

Aminocarbonyl groups are groups of the formula RR′NC(O)—, wherein R orR′ may be the same or different, and each is independently selected fromH, or substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclylor heteroaryl groups, as defined above.

In general, “substituted” refers to a group as defined above in whichone or more bonds to a hydrogen atom contained therein are replaced by abond to non-hydrogen or non-carbon atoms such as, but not limited to, ahalogen atom such as F, Cl, Br, and I; an oxygen atom in groups such ashydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; asulfur atom in groups such as thiol groups, alkyl and aryl sulfidegroups, sulfone groups, sulfonyl groups, and sulfoxide groups; anitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as in trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.Substituted alkyl groups and also substituted cycloalkyl groups andothers also include groups in which one or more bonds to a carbon(s) orhydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen incarbonyl, carboxyl, and ester groups; nitrogen in groups such as imines,oximes, hydrazones, and nitriles.

Substituted cycloalkyl, substituted aryl, substituted heterocyclyl andsubstituted heteroaryl also include rings and fused ring systems inwhich a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted cycloalkyl, substituted aryl, substitutedheterocyclyl and substituted heteroaryl groups may also be substitutedwith alkyl groups as defined above.

Pharmaceutically acceptable salts include a salt with an inorganic base,organic base, inorganic acid, organic acid, or basic or acidic aminoacid. As salts of inorganic bases, the invention includes, for example,alkali metals such as sodium or potassium, alkali earth metals such ascalcium and magnesium or aluminum, and ammonia. As salts of organicbases, the invention includes, for example, trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine. As salts of inorganic acids, the instant inventionincludes, for example, hydrochloric acid, hydroboric acid, nitric acid,sulfuric acid, and phosphoric acid. As salts of organic acids, theinstant invention includes, for example, formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lacticacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.As salts of basic amino acids, the instant invention includes, forexample, arginine, lysine and ornithine. Acidic amino acids include, forexample, aspartic acid and glutamic acid.

The term “protected” with respect to hydroxyl groups, amine groups, andsulfhydryl groups refers to forms of these functionalities which areprotected from undesirable reaction with a protecting group known tothose skilled in the art such as those set forth in Protective Groups inOrganic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, NewYork, N.Y., (3rd Edition, 1999) which can be added or removed using theprocedures set forth therein. Examples of protected hydroxyl groupsinclude, but are not limited to, silyl ethers such as those obtained byreaction of a hydroxyl group with a reagent such as, but not limited to,t-butyldimethyl-chlorosilane, trimethylchlorosilane,triisopropylchlorosilane, triethylchlorosilane; substituted methyl andethyl ethers such as, but not limited to methoxymethyl ether,methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether,2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethylether, allyl ether, benzyl ether; esters such as, but not limited to,benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.Examples of protected amine groups include, but are not limited to,amides such as, formamide, acetamide, trifluoroacetamide, and benzamide;imides, such as phthalimide, and dithiosuccinimide; and others. Examplesof protected sulfhydryl groups include, but are not limited to,thioethers such as S-benzyl thioether, and S-4-picolyl thioether;substituted S-methyl derivatives such as hemithio, dithio and aminothioacetals; and others.

Prodrugs, as used in the context of the instant invention, includesthose derivatives of the instant compounds which undergo in vivometabolic biotransformation, by enzymatic or nonenzymatic processes,such as hydrolysis, to form a compound of the invention. Prodrugs can beemployed to improve pharmaceutical or biological properties, as forexample solubility, melting point, stability and related physicochemicalproperties, absorption, pharmacodynamics and other delivery-relatedproperties.

The instant invention provides potent and specific agonists of MC4-Rthat are small molecules and may exhibit reduced bioaccumulationproperties when administered to animal subjects. In accordance with oneaspect of the invention, the invention provides compounds of formula IA,IB, mixtures thereof, and pharmaceutically acceptable salts thereof.Compounds provided by the invention further include prodrugs of thecompound of formula IA and IB, pharmaceutically acceptable saltsthereof, stereoisomers thereof, tautomers thereof, hydrates thereof, andsolvates thereof. Compounds of formula IA or IB have the followingstructures:

In compounds of formula IA and IB, R¹ is selected from substituted orunsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, or alkyl groups. In some embodiments, R¹ is a substituted orunsubstituted arylalkyl group such as a substituted or unsubstitutedphenylethyl group. In some such embodiments, RR is a substitutedphenylethyl group such as a 4-substituted phenylethyl group or a2,4-disubstituted phenylethyl group such as 4-halophenylethyl,2-halo-4-alkoxyphenylethyl, and 2,4-dihalophenylethyl groups. In someembodiments, R¹ is selected from phenylethyl, 2,4-dichlorophenylethyl,4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl,4-methylphenylethyl, 4-chlorophenylethyl, 4-fluorophenylethyl,4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl,2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl,3-fluorophenylethyl, thienylethyl, indolylethyl, 4-hydroxyphenylethyl,3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl,2-fluoro-4-methylphenylethyl, 4-chloro-2-fluorophenylethyl,4-bromo-2-fluorophenylethyl, 2-fluoro-4-methoxyphenylethyl,2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl,2,4-dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2-pyridyl)ethyl,(3-pyridyl)ethyl, (4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, and(phenyl)(hydroxymethyl)ethyl groups. In still other embodiments, R¹ isselected from 2-fluoro-4-methoxyphenylethyl,2-chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, 4-chlorophenylethyl,4-chloro-2-fluorophenylethyl, 2,4-dichlorophenylethyl,4-bromophenylethyl, or 4-bromo-2-fluorophenylethyl group. In still otherembodiments, R¹ is selected from phenylethyl, 2,4-dichlorophenylethyl,4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl,4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl,cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl,2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl,thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl,2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl,2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromophenylethyl,2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl,2,4-difluorophenylethyl, 2,4-dimethylphenylethyl,2,4-dimethoxyphenylethyl, (2-pyridyl)ethyl, (3-pyridyl)ethyl,(4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl,(phenyl)(hydroxymethyl)ethyl, substituted and unsubstituted(heteroaryl)(hydroxymethyl)ethyl, substituted and unsubstituted(aryl)(hydroxymethyl)ethyl groups, substituted and unsubstituted(aryl)(alkoxymethyl)ethyl, substituted and unsubstituted(aryl)(aryloxymethyl)ethyl, substituted and unsubstituted(aryl)(arylalkoxymethyl)ethyl, substituted and unsubstituted(aryl)(heteroaryloxymethyl)ethyl, substituted and unsubstituted(aryl)(heterocyclyloxymethyl)ethyl, substituted and unsubstituted(heteroaryl)(alkoxymethyl)ethyl, substituted and unsubstituted(heteroaryl)(aryloxymethyl)ethyl, substituted and unsubstituted(heteroaryl)(arylalkoxymethyl)ethyl, substituted and unsubstituted(heteroaryl)(heteroaryloxymethyl)ethyl, and substituted andunsubstituted (heteroaryl)(heterocyclyloxymethyl)ethyl groups.

In compounds of formula IA and IB, R² is selected from H or substitutedor unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino,dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl,heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups.Compounds of formula IA and IB with R² values such as those set forthabove have been found to exhibit reduced bioaccumulation properties asevidenced by lower t_(1/2) blood plasma values in test subjects to whichthe compounds have been administered. Generally, such compounds alsoprovide improved plasma C_(max) values and may also provide improvedbrain C_(max) values. In some embodiments, R² is selected fromsubstituted or unsubstituted heterocyclyl groups or substituted orunsubstituted heteroaryl groups. In other embodiments, R² is selectedfrom substituted or unsubstituted pyridinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl,pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl,indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl groups. Insome such embodiments, R² is selected from heteroaryl or heterocyclylgroup of formula

which may be additionally substituted or may be unsubstituted. In someembodiments, the invention provides compounds of formula IA and IB inwhich R² is selected from substituted or unsubstitutedheterocyclylalkyl, or cycloalkylamino groups. For example, in someembodiments, R² is selected from a group such as a substituted orunsubstituted cyclopropylamino group; a substituted or unsubstitutedpiperazinylalkyl group such as a piperazinylmethyl group or anN-methylpiperazinylmethyl group; or a piperidinylalkyl group such as apiperidinylmethyl group or a piperidinylethyl group. In someembodiments, R² may be selected from a substituted or unsubstituted arylor cycloalkyl group. Examples include compounds of the following formulawhich may be additionally substituted.

In compounds of formula IA and IB, R³, R⁴, and R⁵ are independentlyselected from H, Cl, I, F, Br, OH, NH₂, CN, NO₂, or substituted orunsubstituted alkoxy or alkyl groups. In some embodiments, each of R³,R⁴, and R⁵ are H.

In compounds of formula IA and IB, Z is a piperazinone of formula

which may be additionally substituted. In some embodiments, Z is apiperazinone of formula

In some such embodiments, Z is a piperazinone of formula

Compounds of formula IA and IB with Z values such as those set forthabove have been found to exhibit reduced bioaccumulation properties asevidenced by lower t_(1/2) blood plasma values in test subjects to whichthe compounds have been administered. Generally, such compounds alsoprovide improved plasma C_(max) values and may also provide improvedbrain C_(max) values and intracerebroventricular (icv) efficacy.Significant reductions in FI (food intake) at 16 hours and 30 mpK(mg/kg) were also observed in some subjects for some compounds offormula IA and IB. Compounds of formula IA and IB have been foundparticularly suitable as possessing reduced bioaccumulation properties.Examples of such compounds are set forth in the various embodimentsdescribed above.

In compounds of formula IA and IB, R^(3′) is selected from H orsubstituted or unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl,heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl,or cycloalkylalkyl groups. In some embodiments, R³ is selected fromsubstituted or unsubstituted cycloalkyl groups. In some embodiments,R^(3′) is selected from the group consisting of substituted andunsubstituted cyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl,2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl,2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl,4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, 2-aminocyclohexyl,3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminocyclohexyl,2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl,2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl,3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl,2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl,2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl,3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl,2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl,2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl,2,2-dialkylthiocyclohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl,trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl,cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl,2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl,carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and decalinyl groups.In still other embodiments, R^(3′) is selected from the group consistingof substituted and unsubstituted cyclohexyl, 2-methylcyclohexyl,2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl,2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl,3-methylcyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl,4-t-butylcyclohexyl, isopinocampheyl, 7,7-dimethylnorbornyl,4-isopropylcyclohexyl, 3-methylcycloheptyl groups,2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl,4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethylcyclohexyl,2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl,trifluoromethyl(polycyclic cycloalkyl), fluoromethyl(polycycliccycloalkyl), and fluoro(polycyclic cycloalkyl) groups. In someembodiments, R^(3′) is a substituted or unsubstituted polycycliccycloalkyl group. In some such embodiments, R^(3′) is a substituted orunsubstituted polycyclic cycloalkyl group having the formula II

Compounds of formula IA and IB may exhibit reduced bioaccumulationproperties in animal subjects to which they are administered. Suchsubjects may include human and non-human animal subjects. Examples ofmammalian subjects include, but are not limited to, rodents such as miceand rats, bovines, equines, canines, felines, rabbits, guinea pigs,porcines, primates such as humans and monkeys, and the like. In someembodiments, the invention provides compounds in which the t_(1/2) valuefor the compound is less than 35, 30, 25, 20, 15, 10, or 5 hours in atissue with high blood perfusion such as brain, liver, kidney, andheart. In some such embodiments, the t_(1/2) value for the compound isless than 4 hours and in some embodiments is less than or about 3 hoursin a tissue of a subject to which the compound has been administered.

One or more compounds of the invention may be included in pharmaceuticalformulations or medicaments. Such compositions include at least onecompound of formula IA and/or IB and a pharmaceutically acceptablecarrier. Therefore, the compounds of formula IA and IB may be used toprepare medicaments and pharmaceutical formulations for use in treatingan MC4-R mediated disease such as, but not limited to, obesity, type IIdiabetes, erectile dysfunction, polycystic ovary disease, and SyndromeX. In some embodiments, the MC4-R mediated disease is obesity or type IIdiabetes.

Methods for treating MC4-R mediated diseases include administering to asubject in need thereof, a compound or composition of the instantinvention. In some such embodiments, the compounds of the inventionexhibit reduced bioaccumulation in the tissues such as in the brain orblood plasma of a subject. Administration of the compounds andcompositions of the invention may be accomplished using various methodssuch as those described herein. In one embodiment, the compound orcomposition is administered intranasally.

The instant compounds may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. In some cases, one stereoisomer may be moreactive and/or may exhibit beneficial effects in comparison to otherstereoisomer(s) or when separated from the other stereoisomer(s).However, it is well within the skill of the ordinary artisan toseparate, and/or to selectively prepare said stereoisomers. Accordingly,“stereoisomers” of the instant invention necessarily includes mixturesof stereoisomers, individual stereoisomers, or optically active forms.

The instant invention also provides for compositions which may beprepared by mixing one or more compounds of the instant invention, orpharmaceutically acceptable salts or tautomers thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like, to treat or ameliorate a variety of disorders. Examples ofsuch disorders include, but are not limited to obesity, erectiledisorders, cardiovascular disorders, neuronal injuries or disorders,inflammation, fever, cognitive disorders, sexual behavior disorders. Atherapeutically effective dose further refers to that amount of one ormore compounds of the instant invention sufficient to result inamelioration of symptoms of the disorder. The pharmaceuticalcompositions of the instant invention can be manufactured by methodswell known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, emulsifying or levigatingprocesses, among others. The compositions can be in the form of, forexample, granules, powders, tablets, capsules, syrup, suppositories,injections, emulsions, elixirs, suspensions or solutions. The instantcompositions can be formulated for various routes of administration, forexample, by oral administration, by intranasal administration, bytransmucosal administration, by rectal administration, or subcutaneousadministration as well as intrathecal, intravenous, intramuscular,intraperitoneal, intranasal, intraocular or intraventricular injection.The compound or compounds of the instant invention can also beadministered in a local rather than a systemic fashion, such asinjection as a sustained release formulation. The following dosage formsare given by way of example and should not be construed as limiting theinstant invention.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant invention, or pharmaceuticallyacceptable salts or tautomers thereof, with at least one additive orexcipient such as a starch or other additive. Suitable additives orexcipients are sucrose, lactose, cellulose sugar, mannitol, maltitol,dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides, methyl cellulose,hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. Optionally,oral dosage forms can contain other ingredients to aid inadministration, such as an inactive diluent, or lubricants such asmagnesium stearate, or preservatives such as paraben or sorbic acid, oranti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, a thickeners, buffers, a sweeteners,flavoring agents or perfuming agents. Additionally, dyestuffs orpigments may be added for identification. Tablets and pills may befurther treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions,slurries and solutions, which may contain an inactive diluent, such aswater. Pharmaceutical formulations may be prepared as liquid suspensionsor solutions using a sterile liquid, such as, but not limited to, anoil, water, an alcohol, and combinations of these. Pharmaceuticallysuitable surfactants, suspending agents, emulsifying agents, may beadded for oral or parenteral administration.

As noted above, suspensions may include oils. Such oils include, but arenot limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

For intranasal administration (e.g., to deliver compounds to the brain),or administration by inhalation (e.g., to deliver compounds through thelungs), the pharmaceutical formulations may be a solution, a spray, adry powder, or aerosol containing any appropriate solvents andoptionally other compounds such as, but not limited to, stabilizers,antimicrobial agents, antioxidants, pH modifiers, surfactants,bioavailability modifiers and combinations of these. Examples ofintranasal formulations and methods of administration can be found in WO01/41782, WO 00/33813, WO 91/97947, U.S. Pat. No. 6,180,603, U.S. Pat.No. 5,624,898; Published U.S. Patent Application No. 2003/0229025 (U.S.Ser. No. 10/374,507); and WO 03/072056 each of which is herebyincorporated by reference in its entirety and for all purposes as iffully set forth herein. A propellant for an aerosol formulation mayinclude compressed air, nitrogen, carbon dioxide, or a hydrocarbon basedlow boiling solvent. The compound or compounds of the instant inventionare conveniently delivered in the form of an aerosol spray presentationfrom a nebulizer or the like.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which may be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms may be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation may be a powder suitablefor reconstitution with an appropriate solution as described above.Examples of these include, but are not limited to, freeze dried, rotarydried or spray dried powders, amorphous powders, granules, precipitates,or particulates. For injection, the formulations may optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

For rectal administration, the pharmaceutical formulations may be in theform of a suppository, an ointment, an enema, a tablet or a cream forrelease of compound in the intestines, sigmoid flexure and/or rectum.Rectal suppositories are prepared by mixing one or more compounds of theinstant invention, or pharmaceutically acceptable salts or tautomers ofthe compound, with acceptable vehicles, for example, cocoa butter orpolyethylene glycol, which is present in a solid phase at normal storingtemperatures, and present in a liquid phase at those temperaturessuitable to release a drug inside the body, such as in the rectum. Oilsmay also be employed in the preparation of formulations of the softgelatin type and suppositories. Water, saline, aqueous dextrose andrelated sugar solutions, and glycerols may be employed in thepreparation of suspension formulations which may also contain suspendingagents such as pectins, carbomers, methyl cellulose, hydroxypropylcellulose or carboxymethyl cellulose, as well as buffers andpreservatives.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instantinvention. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

The formulations of the invention may be designed for to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

The instant compositions may also comprise, for example, micelles orliposomes, or some other encapsulated form, or may be administered in anextended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations may be compressedinto pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms. Specific dosages may beadjusted depending on conditions of disease, the age, body weight,general health conditions, sex, diet of the subject, dose intervals,administration routes, excretion rate, and combinations of drugs. Any ofthe above dosage forms containing effective amounts are well within thebounds of routine experimentation and therefore, well within the scopeof the instant invention. A therapeutically effective dose may varydepending upon the route of administration and dosage form. Thepreferred compound or compounds of the instant invention is aformulation that exhibits a high therapeutic index. The therapeuticindex is the dose ratio between toxic and therapeutic effects which canbe expressed as the ratio between LD₅₀ and ED₅₀. The LD₅₀ is the doselethal to 50% of the population and the ED₅₀ is the dose therapeuticallyeffective in 50% of the population. The LD₅₀ and ED₅₀ are determined bystandard pharmaceutical procedures in animal cell cultures orexperimental animals.

The present invention also provides methods of enhancing MC4-R activityin a human or non-human animal. The method comprises administering aneffective amount of a compound, or composition, of the instant inventionto said mammal or non-human animal. Effective amounts of the compoundsof the instant invention include those amounts that activate MC4-R whichare detectable, for example, by an assay described below in theillustrative Examples, or any other assay known by those skilled in theart that a detect signal transduction, in a biochemical pathway, throughactivation of G-protein coupled receptors, for example, by measuring anelevated cAMP level as compared to a control model. Accordingly,“activating” means the ability of a compound to initiate a detectablesignal. Effective amounts may also include those amounts which alleviatesymptoms of a MC4-R disorder treatable by activating MC4-R.

An MC4-R disorder, or MC4-R-mediated disease, which may be treated bythose methods provided, include any biological disorder or disease inwhich MC4-R is implicated, or which inhibition of MC4-R potentiates abiochemical pathway that is defective in the disorder or disease state.Examples of such diseases are obesity, erectile disorders,cardiovascular disorders, neuronal injuries or disorders, inflammation,fever, cognitive disorders, type II diabetes, polycystic ovary disease,Syndrome X, complications from obesity and diabetes, and sexual behaviordisorders. In a preferred embodiment, the instant invention providescompounds, compositions, and methods effective for reducing energyintake and body weight; reducing serum insulin and glucose levels;alleviating insulin resistance; and reducing serum levels of free fattyacids. Accordingly, the instant invention is particularly effective intreating those disorders or diseases associated with obesity or type IIdiabetes.

“Treating” within the context of the instant invention, therefore, meansan alleviation of symptoms associated with a disorder or disease, orhalt of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder. For example,within the context of obesity, successful treatment may include analleviation of symptoms or halting the progression of the disease, asmeasured by reduction in body weight, or a reduction in amount of foodor energy intake. In this same vein, successful treatment of type I ortype II diabetes may include an alleviation of symptoms or halting theprogression of the disease, as measured by a decrease in serum glucoseor insulin levels in, for example, hyperinsulinemic or hyperglycemicpatients.

Scheme 1a illustrates a general synthetic route that may be used tosynthesize various guanidinyl-substituted quinazolinone compounds. Asshown in Scheme 1a, nitro and amino quinazolinone compounds such as (d)and (e) may be readily converted into a plethora of guanidinylquinazolinones by converting the amino functionality to anisothiocyanate functionality such as possessed by compound (f). This maybe accomplished reacting the amine group with thiophosgene.Isothiocyanate compounds such as (f) may then be readily converted intoa thiourea such as compound (g) by reaction with a suitable aminecompound such as (1S,2S,3S,5R)-(+)-isopinocampheylamine. Preparation ofthe desired guanidinylamine such as compound (h) may then beaccomplished by reacting the thiourea with a compound such as1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride and thenwith a suitable amine such as cis-2,6-dimethylpiperazine,(S)-2-(fluoromethyl)piperazine, or the like. Variousfluorine-substituted compounds may be prepared using the methodologyshown in Scheme 1a using an appropriately substituted 4-nitroanthranilicacid. Other compounds may be prepared by using 5-nitroanthranilic acidin place of 4-nitroanthranilic acid.

Scheme 1b illustrates another generally applicable method that may beemployed to synthesize a large number of guanidinyl-substitutedquinazolinones and heterocyclic derivatives of such compounds where acarbon of the benzene ring of the quinazolinone is replaced with anitrogen atom. As shown in Scheme 1b, conversion of compound (d) to (e)may be accomplished by initially adding trimethylphosphine to form areactive iminophosphorane intermediate, adding a substituted isocyanatesuch as a cycloalkyl isocyanate for example, a polycyclic isocyanate toproduce a carbodiimide, and finally forming (e) by addition of andreaction with an amine such as, but not limited to a substitutedpiperazine.

Scheme 2a illustrates another general procedure that may be used toprepare a wide variety of guanidinyl-substituted quinazolinonecompounds.

Scheme 2b shows yet another alternative route that may be used toprepare various compounds of of the invention.

Still another route that may be used to prepare various compounds of theinvention is depicted in Scheme 2c.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

EXAMPLES

The following abbreviations and terms are used throughout the Examples:

-   Boc: t-Butyl carbamate protecting group-   Celite®: Diatomaceous earth filter agent-   DAST: (Dimethylamino)sulfur trifluoride-   DCM: Dichloromethane-   DIBAL: Diisobutylaluminum hydride-   DIEA: N,N-Diisoproylethylamine-   DMF: N,N-Dimethylformamide-   DMSO: Dimethylsulfoxide-   EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOAc: Ethyl acetate-   EtOH: Ethanol-   Gold's Reagent: (Dimethylaminomethyleneaminomethylene)dimethyl    ammonium chloride-   HOBt: Hydroxybenzotriazole-   HPLC: High perfomance liquid chromatography-   HCl: Hydrochloric acid-   HBTU: O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   KOH: Potassium hydroxide-   LC: Liquid Chromatography-   MS: Mass Spectroscopy-   MeOH: Methanol-   mL: Milliliter-   NMO: N-Morpholine oxide-   NMP: 1-Methyl-2-pyrrolidinone-   NMR: Nuclear magnetic resonance spectroscopy-   PS-CDI: Polymer supported carbodiimide resin-   TFA: Trifluoroacetic acid-   THF: Tetrahydrofuran

Synthesis of 6-methylpiperazin-2-one

Step 1: Synthesis of N-Boc-alanine-N′-benzyl Glycine Methyl Ester (1)

To a stirred solution of N-Boc-L-alanine (1 equivalent) and N-benzylglycine methyl ester (1 equivalent) in dichloromethane was added TEA (1equivalent) and HOBt (1 equivalent), followed by EDCI (1 equivalent).The solution was allowed to stir at room temperature under N₂ for 48hours. The reaction was diluted with 10% HCl, and the organic layer wasseparated and dried over MgSO₄. Crude product was chromatographed onsilica (30% EtOAc/hexanes) giving the desired product (1) as a clear oil(75%).

Step 2. Synthesis of[benzyl-(2-tertbutoxycarbonylamino-propyl)-amino]-acetic Acid MethylEster (2)

To a stirred solution of BH₃ in THF (1 M, 2 equivalents), was addeddropwise a solution of dipeptide (1) in THF. The reaction was thenmaintained at room temperature for 24 hours and then diluted withmethylene chloride, washed with NaHCO₃, and dried over MgSO₄. Crudeproduct was chromatographed on silica eluting with 20% EtOAc/hexanesgiving the desired product (2) a colorless oil (40%).

Step 3. Synthesis of 1-benzyl-5-(S)-methyl-3-oxo-piperazine (3)

Ester (2) was stirred in a 50:50 solution of TFA:CH₂Cl₂ for 1 hour. Thesolvent was then removed, and the residue was redissolved in methylenechloride and washed with a saturated solution of Na₂CO₃. The organiclayer was then separated and dried over MgSO₄ giving desired piperazinecompound (3) as a white solid (87%).

Step 4. Synthesis of 6-(S)-methylpiperazin-2-one (4)

To a dichloroethane solution of 3 at room temperature was added 3equivalents of chloroethylchloroformate and Hunig's base (3equivalents). The solution was stirred overnight, and the reaction wasthen directly loaded onto a silica gel column and chromatographedeluting with EtOAc/hexanes (4:6). The isolated carbamate intermediatewas dissolved in methanol and heated at reflux for 2 hours. Removal ofmethanol provided the desired piperazin-2-one (4) as an off white solid(yield was not optimized, but was approximately 60% for the 2 steps).6(S)-methyl piperazin-2-one compounds of the invention were madeaccording to the following methods by EDC activation of the thioureaintermediate to the carbodiimide followed by coupling with 6(S)-methylpiperazin-2-one.

Synthesis of 6-(S)-methylpiperazin-2-one Guanidine Compounds

6(S)-Methyl piperazin-2-one guanidine compounds of the invention wereprepared according to the methods described herein by EDC activation ofthe thiourea intermediate to provide the carbodiimide followed bycoupling with 6(S)-Methyl piperazin-2-one.

Synthesis of 2-(R)-fluoromethylpiperazine and2-(R)-difluoromethylpiperazine

Step 1. Synthesis of N-benzyl Serine Methyl Ester

To a stirred solution of serine methyl ester hydrochloride (3.0 g, 19.28mmol) and triethylamine (2.7 mL, 19.28 mmol) in methylene chloride (30mL) was added benzaldehyde (1 equivalent), followed by 2 g anhydrousMgSO₄. The mixture was stirred at room temperature in a sealed flask for20 hours, and then the solids were filtered away, and the filtrate wasevaporated. The residue was redissolved in methanol (50 mL), and sodiumborohydride (1 equivalent) was carefully added. The mixture was stirredfor 30 minutes, was diluted with methylene chloride, was washed withNaHCO₃, and was then dried over magnesium sulfate. The desired titleproduct was obtained as a yellow oil and was used crude.N-4-methoxybenzyl serine methyl ester was made in a similar fashionusing anisaldehyde in place of benzaldehyde.

Step 2. Synthesis of N-benzyl-N-chloroacetyl Serine Methyl Ester

To an ice cooled solution of the crude benzyl amino acid prepared asdescribed in Step 1 and triethylamine (1 equivalent) in methylenechloride, was added chloroacetyl chloride (1 equivalent) dropwise. After1 hour, the reaction was washed with 10% HCl, and the organic layer wasseparated and dried over sodium sulfate. Crude product waschromatographed on silica gel eluting with 60% EtOAc/hexanes (Rf=0.3)giving the desired title compound as a colorless oil (67%).

Step 3. Synthesis of di-N-benzyl Cyclo Serine Glycine

The chloride prepared in Step 2 was dissolved in acetonitrile, andbenzyl amine was added (3 equivalents). The solution was heated atreflux for 20 hours, during which time a solid formed in the flask. Thereaction was cooled, and the solvent was removed. The residue wasdissolved in methylene chloride, was washed with 10% HCl, and was driedover MgSO₄. Crude product was passed through a silica gel plug (100%EtOAc, Rf=0.5) giving a white solid (80%). Di-N-4-methoxybenzyl cycloserine glycine was made in a similar fashion using p-methoxybenzyl amineand the p-methoxybenzyl derivative of the starting material.

Step 4. Synthesis of 1,4-dibenzyl-2-(R)-piperazinemethanol

To an ice cooled mixture of LiAlH₄ (10 equivalents) in anhydrous THFunder N₂ was added the cyclic dipeptide produced in Step 3 in THFdropwise. The resulting grey mixture was heated to reflux for 16 hours.The reaction was carefully quenched with H₂O, NaOH, H₂O (1:1:3), and theresulting white mixture was filtered through celite. The filtrate wasdried over MgSO₄ and concentrated, giving the desired product as acolorless oil (93%).

Step 5. Synthesis of 1,4-dibenzyl-2-(R)-fluoromethylpiperazine

To an ice cooled solution of DAST (2 equivalents) in methylene chlorideunder N₂ was added the alcohol prepared in Step 4 in methylene chloridedropwise. The yellow solution was stirred at 0° C. to room temperaturefor 20 hours. The reaction was diluted with NaHCO₃, and the organiclayer was separated and dried over sodium sulfate. The crude product waschromatographed on silica gel eluting with 10-50% EtOAc/hexanes givingthe desired title compound as a yellow oil (40%).

Step 6 Synthesis of 2-(R)-fluoromethylpiperazine

1,4-Dibenzylfluoromethylpiperazine from Step 5 was dissolved indichloroethane, and x-chloroethyl chloroformate (3 equivalents) wasadded. The resulting solution was heated to reflux for 16 hours. Thereaction was directly loaded onto a silica gel column andchromatographed eluting with 10-20% EtOAc/hexanes. The intermediatedicarbamate was isolated as a clear oil. The intermediate dicarbamateoil was dissolved in methanol and heated at reflux for 2 hours. Thesolvent was then thoroughly removed giving the desired deprotectedpiperazine as a white solid (90% for 2 steps).

Synthesis of 1,4-di-p-methoxybenzyl-2-(R)-piperazine-carboxaldehyde1,4-di-p-methoxybenzyl-2-(R)-difluoromethylpiperazine

To a dry flask containing a solution of oxalyl chloride in methylenechloride (2.0 M, 1.2 equivalents) at −78° C. was added DMSO (2.4equivalents) dropwise under a stream of nitrogen. After stirring for 15minutes, a solution of 1,4-di-p-methoxybenzyl-2-(R)-piperazinemethanol(1 equivalent) in methylene chloride was added dropwise, and theresulting solution was stirred for 1 hour. TEA (5 equivalents) wasadded, and the mixture was added to NaHCO₃(aq), separated, and driedover MgSO₄. After filtering, the filtrate was cooled to −78° C., andDAST was added dropwise (1.2 equivalents). The resulting orange solutionwas stirred for 12 hours. The reaction was then diluted with aqueoussodium bicarbonate, and the organic layer was separated andchromatographed in silica (10% EtOAc/hexanes) giving the desired titledifluoro compound as a light brown oil (33%). Deprotection of thedifluoride was carried out in the same manner as described in Step 6using α-chloroethyl chloroformate giving a white solid (85%).

Synthesis of 2-(R)-fluoromethylpiperazine and2-(R)-difluoromethylpiperazine Guanidine Compounds

2-(R)-Fluoromethylpiperazine and 2-(R)-difluoromethylpiperazineguanidine compounds of the invention were prepared according to themethods described herein by EDC activation of the thiourea intermediateto provide the carbodiimide followed by coupling with2-(R)-fluoromethylpiperazine or 2-(R)-difluoromethylpiperazine.

Synthesis of (6S)-6-methylpiperazin-2-one)

Step 1. Synthesis ofS-ethyl(2R)-2-{[(benzyloxy)carbonyl]-amino}propanethioate

A 250 mL round bottom flask was charged with benzyloxy-carbonyl-Lalanine (15.0 g, 67.2 mmol) and 67.2 mL of dichloromethane. To thismixture was added DMAP (0.82 g, 6.72 mmol) and chilled EtSH (0° C., 5.46mL, 73.9 mmol) followed by the addition of DCC (15.2 g, 73.9 mmol) inone portion. The addition of the DCC is highly exothermic so thereaction will bubble upon addition, and the reaction should be kept wellvented. The resulting mixture was stirred for 30 minutes at 22° C. Theresulting white solid was then removed by vacuum filtration, and thefiltrate was concentrated. Silica Gel chromatography using hexanes withpolarization to 8:1 hexanes/ethyl acetate afforded 93% yield (18.0 g,62.5 mmol) of the desired product as a colorless oil.

Step 2. Synthesis of Benzyl(1R)-1-methyl-2-oxoethylcarbamate

To a stirred solution containingS-ethyl(2R)-2-{[(benzyloxy)carbonyl]amino}-propanethioate (18.9 g, 62.5mmol), wet 10% Pd/C (1.89 g), and acetone (347 mL) at 0° C. was addedtriethylsilane (29.9 mL, 187.5 mmol). The resulting mixture was stirredfor 30 minutes at 0° C. and then filtered through celite using ethylacetate to wash the celite thoroughly. The filtrate was concentrated andpartitioned between acetonitrile (500 mL) and hexanes (150 mL). Thelayers were separated, and the acetonitrile phase was washed once withhexane (150 mL) and then concentrated to provide the desired product(59.4 mmol, 95%) which was used in the next step without furtherpurification.

Step 3. Synthesis of MethylN-((2R)-2-{[(benzyloxy)carbonyl]-amino}propyl)glycinate

A 1000 mL round bottom flask was charged withbenzyl(1R)-1-methyl-2-oxoethylcarbamate (59.4 mmol) and 347 mL ofanhydrous methanol. The resulting mixture was cooled to 0° C. andglycine methyl ester hydrochloride (29.3 g, 237.6 mmol) was added. After10 minutes, 1.0 M NaCNBH₄ in THF (95 mL, 95.0 mmol) was added and thereaction was allowed to warm to 22° C. overnight. The reaction mixturewas then concentrated, redissolved in diethyl ether (200 mL) and placedin a separatory funnel. The organic phase was washed with saturatedNaHCO₃ (200 mL) and separated. The basic aqueous layer was washed twicewith diethyl ether (2×200 mL), and the combined organic layers werewashed with brine (2×200 mL), dried with Na₂SO₄ and concentrated. Silicagel chromatography using 2:1 hexanes/ethyl acetate with gradualpolarization to 1:1 hexanes/ethyl acetate provided the desired productas a clear oil in 75% yield (12.5 g, 44.6 mmol).

Step 4. Synthesis of (6S)-6-Methylpiperazin-2-one)

To a solution of methylN-((2R)-2-{[(benzyloxy)carbonyl]-amino}propyl)glycinate (12.5 g, 44.6mmol) in anhydrous methanol (446 mL) under an atmosphere of N₂ was added10% Pd/C (1.25 g). The flask was then placed on a Buchi hydrogenator andpurged three times with N₂ followed by 3 times with H₂. The reaction wasallowed to stir under hydrogen (2.2 L, 98.12 mmol) until no morehydrogen was consumed. Once complete (24 hours), the reaction mixturewas poured through Celite and the filtrate was concentrated. Ethylacetate (5-10 mL) was added causing a white solid to crash out. Thiswhite solid was dried and collected to provide the desired product in95% yield (4.8 g, 42.37 mmol). (The filtrate can be concentrated andmore of the product can be crashed out by addition of ethyl acetate. Ifany starting material remains, it will be in the filtrate.

Synthesis of (3R,4R)-3,4-pyrrolidinediol Hydrochloride

(3R,4R)-1-(Phenylmethyl)-3,4-pyrrolidinediol (250 mg, 1.30 mmol) wasdissolved in ethyl acetate and added to a suspension of 10% Pd on carbonin ethyl acetate. The mixture was hydrogenated on a Parr hydrogenator at57 PSI for 12 hours. The reaction was then filtered through Celite toremove catalyst. Excess 4N HCl in dioxane was added and thenconcentrated give the title compound as a brown oil which was usedwithout further purification.

Synthesis of (3S,4S)-3,4-pyrrolidinediol Hydrochloride

(3S,4S)-1-(Phenylmethyl)-3,4-pyrrolidinediol was converted to the titlecompound using the procedure described above for the synthesis of(3R,4R)-3,4-pyrrolidinediol hydrochloride.

Synthesis of Thiomorpholine 1,1-dioxide Hydrochloride

4-(Phenylmethyl)thiomorpholine 1,1-dioxide was converted to the titlecompound using the procedure described above for the synthesis of(3R,4R)-3,4-pyrrolidinediol hydrochloride.

Synthesis of (3R,5R)-5-(hydroxymethyl)-3-pyrrolidinol Trifluoroacetate(Salt)

Step 1. Synthesis of 1-(1,1-Dimethylethyl)2-methyl(2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate

Trimethylsilyl diazomethane (3.89 mmol) was slowly added to an icecooled solution of(4R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-hydroxy-D-proline (0.75 g,3.25 mmol), 60 mL toluene and 20 mL of methanol. The reaction wasstirred for 2 hours on the ice bath, was warmed to room temperature, andwas concentrated to give 0.89 g of the title compound as a clear yellowoil. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.4 (m, 9H), 1.8 (dt, J=12.8, 4.9Hz, 1H), 2.4 (m, 1H), 3.1 (m, 1H), 3.5 (dd, J=10.8, 5.7 Hz, 1H), 3.6 (s,3H), 4.2 (m, 2H).

Step 2. Synthesis of1,1-Dimethylethyl(2R,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate

LiBH₄ (6.46 mmol as a solution in THF) was added to an ice cooledsolution of (1,1-dimethylethyl)2-methyl(2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate (0.36 g, 1.47mmol) in THF. The reaction was heated at 70° C. for 48 hours. Thereaction was quenched with isopropanol and then saturated NaHCO₃. Themixture was diluted with water and extracted twice with ethyl acetate.The organic layers were washed with 1N NaOH, dried over MgSO₄ andconcentrated to give 0.185 g of the title compound. ¹H NMR MHz, DMSO-D6)δ ppm 1.4 (m, 9H), 1.8 (m, 1H), 2.0 (m, 1H), 3.0 (m, 1H), 3.4 (m, 1H),3.5 (m, 2H), 3.7 (m, 1H), 4.1 (m, 1H), 4.9 (dd, J=5.3, 5.3 Hz, 1H), 5.1(m, 1H).

Step 3. Synthesis of (3R,5R)-5-(Hydroxymethyl)-3-pyrrolidinolTrifluoroacetate (Salt)

1,1-Dimethylethyl(2R,4R)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate(0.185 g, 0.852 mmol) was stirred in a 1:1 solution of methylenechloride:TFA for 14 hours. The reaction was concentrated, and the crudematerial was used without further purification. ¹H NMR (400 MHz,DMSO-D6) δ ppm 1.5 (m, 1H), 2.2 (m, 4H), 3.0 (m, 1H), 3.1 (m, 1H), 3.6(m, 3H), 4.3 (m, 1H), 5.3 (s,br, 2H), 8.6 (s,br, 1H), 9.2 (s,br, 1H).

Synthesis of Cis-2,6-dimethyl-piperazine-1-carbonitrile Hydrochloride

Step 1. Synthesis of 4-Cyano-cis-3,5-dimethylpiperazine-1-carboxylicAcid Tert-butyl Ester

4.00 g of cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester(prepared according to the method E. Jon Jacobson et. al. J. Med.Chemistry. 1999, Vol. 42, 1123-144) in 91 mL of dichloromethane wastreated with sodium bicarbonate (4.7 g) followed by addition of cyanogenbromide (7.5 mL). The reaction mixture was heated at reflux overnight,was filtered, and was purified by column chromatography (0 to 50% ethylacetate/hexanes) to afford 3.9 g of the title compound as a white solid.¹H NMR (CDCl₃, 300 MHz) δ ppm 1.33 (d, 6H, J=6.5 Hz), 1.44 (s, 9H), 2.54(m, 2H), 3.09 (m, 2H), 4.09 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) 16.70 (2C),28.54 (3C), 53.86 (4C), 80.86, 114.10, 154.22.

Step 2. Synthesis of cis-2,6-Dimethyl-piperazine-1-carbonitrileHydrochloride

4-Cyano-cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester(1.0 g) in 10 mL THF was treated with 4.0 N HCl/dioxane (25 mL), stirredfor five hours and concentrated to provide 1.1 g of the title compound.¹H NMR (DMSO-D6, 300 MHz) δ ppm 1.24 (d, 6H, J=6.6 Hz), 2.65 (q, 2H,J=11.1 Hz), 3.27 (d, 2H, J=12.2 Hz), 3.63 (m, 2H); ¹³C (DMSO, 75 MHz)16.73 (2C), 46.81 (2C), 50.80 (2C), 104.20.

Synthesis of Cis-2,6-dimethyl-piperazin-1-ol Hydrochloride

Step 1. Synthesis ofCis-3,5-Dimethyl-4-(3-oxo-butyl)-piperazine-1-carboxylic Acid Tert-butylEster

Cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.00 g;prepared according to the method E. Jon Jacobson et. al.: J. Med.Chemistry. 1999, Vol. 42, 1123-144) in 47 mL chloroform was treated withmethylvinylketone (1.7 mL) at room temperature and heated at reflux fortwo days. The reaction was then concentrated, diluted with THF andheated at reflux for 1 day before purifying by column chromatography (0to 10% MeOH/DCM) to afford 0.865 g of the title compound as a clear,colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ ppm 1.08 (d, 2H, J=6.07 Hz),1.47 (s, 9H), 2.17 (s, 3H), 2.52 (m, 6H), 3.10 (m, 2H), 2.86 (bs, 2H);¹³C NMR (CDCl₃, 75 MHz) 17.6 (2C), 28.62 (5C), 30.8, 37.34, 42.46, 53.57(4C), 79.85, 154.49, 208.29.

Step 1. Synthesis of Cis-2,6-Dimethyl-piperazin-1-ol Hydrochloride

Cis-3,5-Dimethyl-4-(3-oxo-butyl)-piperazine-1-carboxylic acid tert-butylester (1.00 g) in chloroform (40 mL) was treated with m-chloroperbenzoicacid (77%, 0.97 g) at 0° C. The solution was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was then cooledto 0° C., filtered to remove precipitates, washed with saturated aqueoussodium bicarbonate, filtered through a plug of silica gel andconcentrated. The residue was taken up in a 1:1 mixture of DCM and MeOHand treated with an excess of 4.0 M HCl/dioxane. The reaction mixturewas stirred overnight and then purified by column chromatography (0 to10% MeOH:DCM) to yield 50 mg of the title compound. ESMS (0.41 minutes,(M+1) 131.13, Method E).

Synthesis of 3-methyl-azetin-3-ol Hydrochloride

Step 1. Synthesis of 1-benzhydryl-azetidin-3-ol

A solution of 1-(diphenylmethyl)-3-(methanesulphonyloxy)azetidine (1.0g) in THF (17 mL) was treated with 3.0 M methylmagnesium bromide (1.2mL) in diethyl ether at 0° C. The reaction was stirred for 1.5 hours at0° C. and then quenched with saturated aqueous sodium bicarbonate,filtered through Celite, and concentrated. The residue was then take upin methylene chloride and washed with saturated aqueous sodiumbicarbonate, followed by brine. The organic layer was dried overmagnesium sulfate, filtered, concentrated and purified by columnchromatography (0 to 60% EtOAc/hexanes) to provide 640 mg of the titlecompounds as a clear, yellow oil. ESMS: 240.19 (M+1), 1.22 minutes,Method D.

Step 2. Synthesis of 1-Benzhydryl-azetidin-3-one

To a solution of 1-benzhydryl-azetidin-3-ol (640 mg) in methylenechloride (6.0 mL) was added 4 Å molecular sieves. The reaction vesselwas purged with nitrogen followed by addition of NMO (800 mg) and thenTPAP (42 mg). The reaction was stirred over night and then filteredthrough a plug of silica to yield 335 mg of the title compound as aclear, colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ ppm 4.03 (s, 4H), 4.61(s, 1H), 7.25 (m, 2H), 7.32 (m, 4H), 7.50 (m, 4H).

Step 3. Synthesis of 1-Benzhydryl-3-methyl-azetidin-3-ol

1-Benzhydryl-azetidin-3-one (335 mg) in diethyl ether (6.0 mL) wastreated with 3.0 M methylmagnesium bromide in diethyl ether (0.52 mL) at0° C., stirred for 10 minutes and quenched with saturated aqueous sodiumbicarbonate. The solution was then extracted with methylene chloride(×3), and the combined organics were dried over magnesium sulfate, andconcentrated to provide 363 mg of the title compound as a clear,colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ ppm 1.53 (s, 3H), 1.96 (s, 1H),1.96 (d, 2H, J=8.42 Hz), 3.19 (d, 2H, J=8.42 Hz), 4.34 (s, 1H), 7.17 (m,2H), 7.26 (m, 2H), 7.31 (m, 2H), 7.40 (m, 4H).

Step 4. Synthesis of 3-Methyl-azetin-3-ol Hydrochloride

A suspension of 1-benzhydryl-3-methyl-azetidin-3-ol (363 mg) in MeOH (10mL) was treated with 4.0 N HCl/dioxane (1.0 mL) followed by an excess ofpalladium hydroxide on carbon (wet, Degusa type). The solution was thenreacted with hydrogen on a Parr hydrogenator over night at 45 psi. Thereaction mixture was then filtered through Celite, concentrated, dilutedto a known concentration and used without further purification.

Synthesis of Piperidin-4-one O-methyl-oxime Hydrochloride

Step 1. Synthesis of 4-Methoxyimino-piperidine-1-carboxylic AcidTert-butyl Ester

A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) andmethoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated withsodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasicmixture was stirred vigorously for 10 minutes, diluted with water, andextracted with ethyl acetate (×3). The combined extracts were dried overmagnesium sulfate, filtered and concentrated to afford 2.12 g of thetitle compound, which was used without further purification. ¹H NMR(CDCl3, 300 MHz) δ ppm 1.49 (s, 9H), 2.34 (t, 2H, J=6.07 Hz), 2.57 (t,2H, J=6.07 Hz), 3.51 (t, 2H, J=6.07 Hz), 3.56 (t, 2H, J=6.07 Hz), 3.85(s, 3H).

Step 2. Synthesis of Piperidin-4-one O-methyl-oxime Hydrochloride

4-Methoxyimino-piperidine-1-carboxylic acid tert-butyl ester in MeOH (10mL) was treated with 4.0 M HCl/dioxane (1.0 mL) and stirred at roomtemperature over night. The solution was concentrated to yield 213 mg ofthe title compound without further purification. ¹H NMR (DMSO, 300 MHz)δ ppm 2.47 (t, 2H, J=6.62 Hz), 2.68 (t, 2H, J=6.07 Hz), 3.17 (m, 4H),3.77 (s, 3H), 9.08 (bs, 1H).

Synthesis of 4-methyl-piperidin-4-ol Hydrochloride

A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (500 mg) in THF(6 mL) at 0° C. was treated with 3.0 M methylmagnesium bromide/diethylether (0.80 mL). The solution was allowed to warm to room temperatureand stirred for 48 hours. The reaction was quenched with sodiumbicarbonate, diluted with saturated Rochele's Salt, and extracted withmethylene chloride (×3). The combined organics were filtered throughCelite, concentrated, and purified by column chromatography (0 to 40%EtOAc/hexanes). The impure residue was then taken up in MeOH (5 mL) andtreated with 4.0 M HCl/dioxane (4 mL), stirred for 30 minutes andconcentrated to provide the crude title compound.

Synthesis of Ethyl(3S)-3-hydroxy-L-prolinate Hydrochloride

Acetyl chloride (10.8 mL, 153 mmol) was slowly added to ice cold 100%Ethanol (100 mL). (3S)-3-hydroxy-L-proline (5 g, 38.2 mmol) was addedand heated at 100° C. for 16 hours. The ester was concentrated to asolid and used without purification. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.2(t, J=8.1 Hz, 3H) 1.9 (m, 2H) 3.3 (m, 2H) 4.1 (m, 1H) 4.2 (q, J=7.1 Hz,2H) 4.4 (m, 1H) 9.0 (s, 1H) 10.4 (s, 1H).

Synthesis of [(2S,3S)-3-methyl-2-pyrrolidinyl]methanol Hydrochloride

Step 1. Synthesis of Ethyl(3S)-3-methyl-L-prolinate

The title compound was prepared from (3S)-3-methyl-L-proline, using themethods used to prepare ethyl(3S)-3-hydroxy-L-prolinate hydrochloride.¹H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.8 Hz, 3H) 1.2 (t, J=6.8 Hz,3H) 1.6 (m, 1H) 2.1 (m, 1H) 2.3 (m, 1H) 3.2 (m, 2H) 3.8 (m, 1H) 4.2 (m,2H) 4.7 (m, 1H) 9.0 (s, 1H) 10.4 (s, 1H).

Step 2. Synthesis of 1-(1,1-Dimethylethyl)2-ethyl(2S,3S)-3-methyl-1,2-pyrrolidinedicarboxylate

Ethyl(3S)-3-methyl-L-prolinate (0.837 g, 4.32 mmol),bis(1,1-dimethylethyl) dicarbonate (0.942 g, 4.32 mmol), andtriethylamine (1.5 mL, 10.8 mmol) were heated in an approximately 2:1mixture of THF and ethanol at 75° C. for 16 hours. The reaction wasallowed to cool to room temperature, then diluted with water. The crudemixture was extracted 2× with ethyl acetate. The organic layers werewashed with 1N NaOH, dried over MgSO₄, and concentrated under reducepressure to give the title compound (855 mg, 3.3 mmol) as a clear oil.¹H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.8 Hz, 3H) 1.2 (m, 3H) 1.3(m, 9H) 1.5 (m, 1H) 1.9 (m, 1H) 2.2 (m, 1H) 3.2 (m, 1H) 3.4 (m, 1H) 3.6(m, 1H) 4.1 (m, 2H).

Step 3. Synthesis of1,1-Dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate

Lithium borohydride (6.6 mmol, 3.31 mL of a 2M in THF solution) wasadded dropwise to an ice cold THF solution of 1-(1,1-dimethylethyl)2-ethyl(2S,3S)-3-methyl-1,2-pyrrolidinedicarboxylate (850 mg, 3.3 mmol)and methanol (0.133 mL, 3.3 mmol). The reaction was warmed to roomtemperature and then stirred for 4 hours. The reaction was quenched withi-propanol then with saturated NaHCO₃. The reaction mixture wasextracted 3× with ethyl acetate. The organic layers were dried overMgSO₄ and concentrated under reduced pressure to give the titlecompound, which was used without further purification. ¹H NMR (400 MHz,DMSO-D6) δ ppm 0.9 (t, J=7.0 Hz, 3H) 1.3 (m, 9H) 1.9 (m, 1H) 2.2 (m, 1H)3.1 (m, 2H) 3.3 (m, 2H) 3.5 (m, 1H) 4.7 (m, 1H).

Step 4. Synthesis of [(2S,3S)-3-Methyl-2-pyrrolidinyl]methanolHydrochloride

The crude1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylatefrom step 3 was dissolved in a 1:1 mixture of methylenechloride:methanol. Excess 4N HCl in dioxane was added, and the reactionstirred at room temperature for 1 hour, concentrated under reducedpressure, and then used in the final step (see Scheme 1a (g) to (h)). ¹HNMR MHz, DMSO-D6) δ ppm 1.1 (d, J=6.2 Hz, 3H) 1.5 (m, 1H) 2.1 (m, 2H)3.1 (m, 1H) 3.3 (m, 1H) 3.4 (m, 1H) 4.5 (dd, J=12.1, 8.1 Hz, 1H) 4.7(dd, J=12.3, 3.1 Hz, 1H).

Synthesis of Ethyl(3S)-3-hydroxy-L-prolinate Hydrochloride

Acetyl chloride (10.8 mL, 153 mmol) was slowly added to ice cold 100%Ethanol (100 mL). (3S)-3-hydroxy-L-proline (5 g, 38.2 mmol) was addedand heated at 100° C. for 16 hours. The ester was concentrated to asolid and used without purification. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.2(t, J=8.1 Hz, 3H) 1.9 (m, 2H) 3.3 (m, 2H) 4.1 (m, 1H) 4.2 (q, J=7.1 Hz,2H) 4.4 (m, 1H) 9.0 (s, 1H) 10.4 (s, 1H).

Synthesis of (2R,3S)-2-methyl-3-pyrrolidinol Hydrochloride

Step 1. Synthesis of 1-(1,1-Dimethylethyl)2-ethyl(2S,3S)-3-hydroxy-1,2-pyrrolidinedicarboxylate

The title compound was prepared from ethyl(3S)-3-hydroxy-L-prolinateusing the methods used to prepare 1-(1,1-dimethylethyl) 2-ethyl(2S,3S)-3-methyl-1,2-pyrrolidinedicarboxylate. ¹H NMR (400 MHz, DMSO-D6)δ ppm 1.2 (m, 3H) 1.3 (m, 9H) 1.7 (m, 1H) 1.9 (m, 1H) 3.3 (m, 2H) 4.1(m, 4H) 5.5 (s, 1H).

Step 2. Synthesis of 1-(1,1-Dimethylethyl)2-ethyl(2S,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1,2-pyrrolidinedicarboxylate

1-(1,1-dimethylethyl)2-ethyl(2S,3S)-3-hydroxy-1,2-pyrrolidinedicarboxylate (8.98 g, 34.7mmol), imidazole (2.36 g, 34.7 mmol), dimethylaminopyridine (50 mg,catalytic) and chloro(1,1-dimethylethyl)dimethylsilane (4.96 g, 32.9mmol) were stirred at room temperature for 16 hours. The reaction wasdiluted with water and 1N HCl to make the mixture acidic. The mixturewas extracted three times with methylene chloride. The organic layer waswashed with 1M HCl, dried over MgSO₄ to give the title compound as aclear brown oil (10.88 g, 29.1 mmol). ¹H NMR (400 MHz, DMSO-D6) δ ppm0.0 (m, 6H) 0.8 (m, 9H) 1.2 (m, 3H) 1.3 (m, 9H) 1.7 (m, 1H) 1.9 (m, 1H)3.4 (m, 2H) 3.9 (m, 1H) 4.1 (m, 2H) 4.4 (m, 1H). ES+=374.30.

Step 3. Synthesis of1,1-Dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate

The title compound was prepared from 1-(1,1-dimethylethyl)2-ethyl(2S,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1,2-pyrrolidinedicarboxylateusing the methods used for preparation of1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate.¹H NMR (400 MHz, DMSO-D6) δ ppm—0.0 (m, 6H) 0.8 (m, 9H) 1.0 (m, 1H) 1.4(m, 9H) 1.6 (m, 1H) 3.1 (m, 1H) 3.2 (m, 2H) 3.5 (m, 2H) 4.3 (m, 1H) 4.8(m, 1H).

Step 4. Synthesis of1,1-Dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylate

Methanesulfonyl chloride (3.85 mL, 39.29 mmol) was added to an ice coldmethylene chloride solution of1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (6.05 g,26.19 mmol) and triethylamine (7.28 mL, 52.38 mmol). The reaction waswarmed to room temperature, stirred for 16 hours then concentrated underreduced pressure. The crude material was dissolved in ethyl acetate andwashed with saturated NaHCO₃, dried over MgSO₄ and concentrated underreduced pressure. The crude material was purified by silica gel columnchromatography to give the title compound as a yellow oil. (4.69 g, 11.4mmol). ¹H NMR (400 MHz, DMSO-D6) δ ppm 0.1 (s, 6H) 0.8 (s, 9H) 1.4 (m,9H) 1.7 (m, 1H) 2.0 (m, 1H) 3.2 (s, 3H) 3.3 (m, 2H) 3.7 (m, 1H) 4.0 (m,1H) 4.2 (m, 1H) 4.3 (m, 0.1H). ES+=410.16.

Step 5. Synthesis of1,1-Dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1-pyrrolidinecarboxylate

Superhydride (45.8 mL, 1M, 45.8 mmol) was added dropwise to an ice coldsolution of1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylate(4.69 g, 11.47 mmol) in THF. The reaction was warmed to room temperatureand stirred for 16 hours. The reaction was quenched with i-propanoluntil gas evolution ceased. The reaction was diluted with saturatedNaHCO₃ then extracted with ethyl acetate, dried over MgSO₄ andconcentrated under reduced pressure. The crude material was purified bysilica gel column chromatography to yield the title compound (2.69 g,8.5 mmol). ¹H NMR (400 MHz, DMSO-D6) δ ppm 0.0 (s, 6H) 0.8 (s, 9 H) 1.0(m, 3H) 1.4 (s, 9H) 1.6 (m, 1H) 2.0 (m, 1H) 3.3 (m, 2H) 3.5 (m, 1H) 4.0(m, 1H). ES+=316.22.

Step 6. Synthesis of1,1-Dimethylethyl(2R,3S)-3-hydroxy-2-methyl-1-pyrrolidinecarboxylate

Tetrabutyl ammonium fluoride (16.7 mL, 1N in THF, 16.73 mmol) was addedto a solution of1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1-pyrrolidinecarboxylatein TH F and stirred for 16 hours at room temperature. The reactionmixture was concentrated under reduced pressure and purified by silicagel column chromatography to yield the title compound (1.55 g, 7.8mmol). ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.0 (m, 3H) 1.4 (s, 9H) 1.6 (m,1H) 1.9 (m, 1H) 3.3 (m, 2H) 3.5 (m, 1H) 3.8 (m, 1H) 4.9 (s, 1H).ES+=202.15.

Step 7. Synthesis of (2R,3S)-2-Methyl-3-pyrrolidinol Hydrochloride

The title compound was prepared from 1,1-dimethylethyl(2R,3S)-3-hydroxy-2-methyl-1-pyrrolidinecarboxylate using the methodsused for preparation of [(2S,3S)-3-methyl-2-pyrrolidinyl]methanolhydrochloride. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=7.0 Hz, 3H) 1.7(m, 1H) 2.1 (m, 1H) 3.2 (m, 2H) 3.3 (m, 1H) 3.9 (m, 1H) 5.5 (m, 1H) 9.0(s, 1H) 9.4 (m, 1H). ES+=101.82.

Synthesis of (2R,3S)-2-(hydroxymethyl)-3-pyrrolidinol Hydrochloride

Step 1. Synthesis of1,1-Dimethylethyl(2R,3S)-3-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate

The title compound was prepared from 1-(1,1-dimethylethyl)2-ethyl(2S,3S)-3-hydroxy-1,2-pyrrolidinedicarboxylate using the methodsused to prepare1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate.¹H NMR (400 MHz, DMSO-D6) δ ppm 1.4 (s, 9H) 1.6 (m, 1H) 1.9 (m, 1H) 3.1(m, 1H) 3.2 (m, 2H) 3.4 (m, 2H) 4.1 (m, 1H). ES+=218.24, 117.97 (-Boc).

Step 2. Synthesis of (2R,3S)-2-(Hydroxymethyl)-3-pyrrolidinolHydrochloride

The title compound was prepared from 1,1-dimethylethyl(2R,3S)-3-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate using themethods used to prepare [(2S,3S)-3-methyl-2-pyrrolidinyl]methanolhydrochloride. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (m, 1H) 2.0 (m, 1H)2.5 (m, 2H) 3.2 (m, 2H) 3.3 (m, 1H) 3.5 (m, 1H) 3.6 (m, 1H) 4.1 (m, 1H)8.7 (s, 1H) 9.5 (m, 1H). ES+=117.97.

Synthesis of N-3-azetidinylmethanesulfonamide

Step 1. Synthesis ofN-[1-(diphenylmethyl)-3-azetidinyl]methanesulfonamide

A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized accordingto the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56,1986)(197 mg, 0.83 mmol) in dichloromethane (10 mL) was treated withexcess triethylamine at 0° C. followed by methanesulfonyl chloride (71μL, 0.91 mmol). The reaction was stirred for 30 minutes and thenconcentrated and purified on silica gel (0-10% methanol/dichloromethane)to provide 185 mg of the desired product as a white solid. LC/MS: M+H317.19 at 0.31 minutes, Method D.

Step 2. Synthesis of N-3-azetidinylmethanesulfonamide

A solution of N-[1-(diphenylmethyl)-3-azetidinyl]-methanesulfonamide(185 mg, 0.585 mmol) in MeOH (10 mL) was treated with 1 mL of 4.0 NHCl/dioxane and then reacted overnight with hydrogen gas at 50 psi. Thereaction mixture was then filtered through a pad of Celite and usedwithout further purification.

Synthesis of (4E)-3-methyl-4-piperidinone-O-methyloxime

Step 1. Synthesis of 1,1-Dimethylethyl3-methyl-4-oxo-1-piperidinecarboxylate

A solution of 3-methyl-1-(phenylmethyl)-4-piperidinone (1.5 g, 7.4 mmol)in methanol (10 mL) was treated with 4.0 N HCl/dioxane (2.2 mL),followed by palladium hydroxide. The mixture was then reacted overnightwith hydrogen gas at 50 psi. The reaction was then filtered throughCelite, concentrated, and then taken up in THF (20 mL). The crudereaction mixture was then treated with triethylamine (2.3 mL), followedby di-tert-butyl dicarbonate (1.9 g, 8.9 mmol). The reaction was stirredfor two hours, concentrated, taken up in dichloromethane and washed withsaturated aqueous ammonium hydroxide, followed by brine. The organiclayer was dried over magnesium sulfate and purified by columnchromatography to provide 734 mg of 1,1-dimethylethyl3-methyl-4-oxo-1-piperidinecarboxylate as a white solid. ¹H NMR (400MHz, CDCl₃) δ ppm 1.0 (d, J=6.69, 3H) 1.5 (s, 9H) 2.4 (m, 2H) 2.5 (m,1H) 2.8 (m, 1H) 3.2 (m, 1H) 4.2 (m, 2H).

Step 2. Synthesis of1,1-Dimethylethyl(4E)-3-methyl-4-[(methyloxy)imino]-1-piperidinecarboxylate

A solution of 1,1-dimethylethyl 3-methyl-4-oxo-1-piperidinecarboxylate(367 mg, 1.72 mmol) in THF (10 mL) was treated with methylhydroxylaminehydrochloride (503 mg, 6.02 mmol) followed by a solution of sodiumhydrogencarbonate (506 mg, 6.02 mmol) in water (3 mL). The reaction wasstirred vigorously overnight. The reaction was then filtered, dilutedwith water, and extracted with dichloromethane. The crude material waspurified by column chromatography (0-10% ethyl acetate/hexanes) toprovide 197 mg of the desired product as a white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.1 (d, J=6.8 Hz, 3H) 1.5 (s, 9H) 2.5 (m, 1H) 2.6 (m, 2H)3.5 (m, 4H) 3.8 (s, 3H).

Step 3. Synthesis of (4E)-3-methyl-4-piperidinone O-methyloxime

1,1-Dimethylethyl(4E)-3-methyl-4-[(methyloxy)imino]-1-piperidinecarboxylate(197 mg) was dissolved in methanol, treated with 4.0 N HCl/dioxane (4mL) and stirred overnight. The reaction was then concentrated to providethe product as a white solid (170 mg). The crude material was usedwithout further purification.

Synthesis of 4,4-dimethylcyclohexanone

The title compound was synthesized using the following literatureprocedure which is hereby incorporated by reference and for all purposesas if fully set forth in its entirety. Liu, Hsing-Jang; Browne, Eric N.C. and Chew, Sew Yeu. Can. J. Chem. 66, 2345-2347 (1988).

Synthesis of (4,4-dimethylcyclohexyl)amine

The title compound was synthesized using the following literatureprocedure which is hereby incorporated by reference and for all purposesas if fully set forth in its entirety. Faller, A., MacPherson, D. T.,Ner, P. H., Stanway, S. J. and Trouw, L. S. WO04/5913A1 (2003).

Synthesis ofN-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]carbodiimide

N-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]thioureawas gently stirred with Argonaut PS-Carbodiimide (1.5 eq) for 15 hoursin THF. The resin was filtered off and the solution of carbodiimide Awas diluted to a known volume to give a solution of known molarity.

Synthesis ofN-{3-[2-(2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]carbodiimide

N-{3-[2-(2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]thioureawas gently stirred with Argonaut PS-Carbodiimide (1.5 eq) for 15 hoursin THF. The resin was filtered off and the solution of carbodiimide Bwas diluted to a known volume to give a solution of known molarity.

Synthesis of2-chloro-3-[2-(2,4-dichlorophenyl)ethyl]-7-nitro-4(3H)-quinazolinone

Step 1. Synthesis of2-Amino-N-[2-(2,4-dichlorophenyl)ethyl]-4-nitrobenzamide

To a stirred solution of 4-nitro-isatoic anhydride (10.0 g, 0.048 mol)in CH₂Cl₂ (100 mL) was added 2,4-dichlorophenethylamine (10.08 g, 0.053mol) followed by DMF (10 mL). The reaction mixture was stirred at roomtemperature for 30 min. The resulting mixture was then dissolved in 1.0L CH₂Cl₂ and washed with 1.0 M NaOH. The combined organic layers wereconcentrated under reduced pressure and purified by silica gel flashchromatography (0-100% EtOAc/hexanes eluent) to give the product (16.5g, 97% yield) as a yellow solid. HPLC retention time: 3.04 min; MethodA; LRMS (ESI) m/z 354 (M+1).

Step 2. Synthesis of3-[2-(2,4-Dichlorophenyl)ethyl]-7-nitro-2,4(1H,3H)-quinazolinedione

To a stirred solution of2-amino-N-[2-(2,4-dichlorophenyl)ethyl]-4-nitrobenzamide (1.0 g, 2.82mmol) in toluene (30 mL) was added a 1.9 M solution of phosgene intoluene (4.5 mL, 8.5 mmol). The reaction mixture was heated to 60° C.and stirred for 4 hours. The solvent was removed under reduced pressureand CH₂Cl₂ was added to the residue. The precipitate was collected viavacuum filtration and washed with CH₂Cl₂ to give the product (0.92 g,86% yield) as a white solid. HPLC retention time: 3.28 min; Method A;LRMS (ESI) m/z 378 (M−1).

Step 3. Synthesis of2-Chloro-3-[2-(2,4-dichlorophenyl)ethyl]-7-nitro-4(3H)-quinazolinone

3-[2-(2,4-Dichlorophenyl)ethyl]-7-nitro-2,4(1H,3H)-quinazolinedione (2.0g, 5.26 mmol) and PCl₅ (1.2 g, 5.79 mmol) were added to a flaskcontaining POCl₃ (20 mL) and the resulting solution was refluxed withstirring for 6 hours. The reaction was allowed to cool to RT and stirredovernight at this temp. The POCl₃ was removed under reduced pressure andCH₂Cl₂ was added to the residue. The unreacted starting material wasremoved via vacuum filtration and the product was purified by silica gelflash chromatography (100% CH₂Cl₂ eluent) to give the product (0.96 g,46% yield) as a white solid. ¹H NMR (DMSO-D6) 400 MHz 6 ppm 8.35-8.25(m, 3H), 7.58 (d, J=2.2 Hz, 1H), 7.41-7.34 (m, 2H), 4.41 (t, J=7.5 Hz,2H), 3.15 (t, J=7.5 Hz, 2H) ppm.

Synthesis of3-amino-N-{3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximidamide

Step 1. Synthesis of1-Dimethylethyl[1-(diphenylmethyl)-3-azetidinyl]carbamate

To a solution of 1-(diphenylmethyl)-3-azetidinamine (232 mg, 0.97 mmol)in THF (6 mL) at 0° C. was added a solution di-tert-butyl dicarbonate(255 mg, 1.17 mmol) in THF (4 mL). The reaction was warmed to roomtemperature and dichloromethane (4 mL) was added to bring the slurryinto solution. The reaction was stirred overnight, concentrated and thenpurified by column chromatography (0-30% ethyl acetate/hexanes) toafford 211 mg of the desired product as a white solid. LC/MS: M+H 339.19at 1.20 minutes, Method D.

Step 2. Synthesis of 1,1-Dimethylethyl 3-azetidinylcarbamate

A solution of1,1-dimethylethyl[1-(diphenylmethyl)-3-azetidinyl]carbamate in MeOH (10mL) was treated with of 4.0 N HCl/dioxane (1 mL) and then reactedovernight with hydrogen gas at 50 psi. The reaction mixture was thenfiltered through a pad of Celite, concentrated and the crude residue wasused without further purification.

Step 3. Synthesis of3-Amino-N-{3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximidamide

1,1-dimethylethyl[1-((Z)-({3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}amino){[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)-3-azetidinyl]carbamate(synthesized using 1,1-dimethylethyl 3-azetidinylcarbamate by themethods described previously) was treated with 4.0 N HCl/dioxane (4 mL)and stirred overnight. The reaction was then purified by preparatoryHPLC to provide3-amino-N-{3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximidamideas a white solid. LC/MS: M+H 517.20 at 2.19 minutes, Method D.

General Method for the Preparation of Nitrogen-Bound C-2 Analogs Step 1.Synthesis of 2-Amino Analogs

To a stirred solution2-chloro-3-[2-(2,4-dichlorophenyl)ethyl]-7-nitro-4(3H)-quinazolinone (1equivalents) in acetonitrile (1.0 M) was added the corresponding amine(2 equivalents) and the reaction mixture was heated to reflux until thereaction was completed as monitored by HPLC (ca. 30 min). The reactionmixture was then cooled to RT and the solvent was removed in vacuo. Thecrude product was purified via silica gel flash chromatography (0-5%MeOH/CH₂Cl₂ eluent).

Step 2. Reduction of Nitro to Aniline

To a stirred solution of the nitro compound (1 equiv) in absoluteethanol (1.0 M) was added iron powder (2.5 equivalents) and acetic acid(14 equivalents). The reaction mixture was heated to reflux until thereaction was complete as monitored by HPLC. The reaction mixture wasthen cooled to RT, diluted with EtOAc, and washed with sat. NaHCO₃. Theaqueous layer was re-extracted with EtOAc (×2) and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude solid was used in the next step without purification.

Step 3. Conversion of Aniline to Thiourea

To a stirred solution of crude aniline (1 equiv) in acetone (1.0 M) at0° C. was added Na₂CO₃ (2 equivalents) followed by thiophosgene (3equivalents) dropwise via syringe. The reaction mixture was stirred at0° C. for 10 minutes then allowed to warm to room temperature. A solidprecipitated from solution as the reaction progressed. When the startingmaterial was completely consumed as monitored by HPLC, the reactionmixture was concentrated in vacuo, diluted with acetone, and thenconcentrated again to remove excess thiophosgene. The material was thendiluted with EtOAc and washed with water. All of the solid wasdissolved. The aqueous layer was re-extracted with EtOAc (×2) and thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was then dissolved in THF (1.0M) and (1S,2S,3S,5R)-(+)-isopinocampheylamine (1.3 equiv) was added viasyringe. The reaction mixture was stirred at RT for 30 min thenconcentrated in vacuo. The crude material was purified via silica gelflash chromatography (0-5% MeOH/CH₂Cl₂ eluent).

Step 4. Conversion of Thiourea to Guanidine

To a stirred solution of thiourea (1 equivalents) in THF (1.0 M) wasadded EDC (1.5 equivalents) and the reaction mixture was heated toreflux. When the starting material was completely consumed as monitoredby HPLC, the reaction mixture was cooled to RT and then thecorresponding amine (2 equivalents) and Et₃N (2 equivalents) were added.The reaction mixture was stirred at room temperature for 1 hour thenconcentrated in vacuo. The crude material was purified via preparativereversed-phase HPLC (MeCN/water eluent) and lyophilized to produce theTFA salt.

General Procedure for the Synthesis of Aryl Guanidines

Unless otherwise noted, a THF solution of a carbodiimide such asCarbodiimide A or Carbodiimide B was stirred with approximately 1.5equivalents of primary or secondary amine at room temperature for 10minutes. (In cases where the amine was in a salt form, the amine wasdissolved in minimal methanol and 2 equivalents of triethylamine wasadded.) The reaction were concentrated under a stream of nitrogen,dissolved in methanol and purified by preparative HPLC.

Synthesis ofN-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′-4H-1,2,4-triazol-4-yl-N″-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]guanidineTrifluoroacetate

N-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]carbodiimide(4 mL, 23 mM solution in THF), 4H-1,2,4-triazol-4-amine (49 mg) andexcess NaH were stirred together and heated at 50° C. for 30 minutes.The reaction was quenched with 1 mL H₂O and 5 mL of ethyl acetate. Themixture was passed through a Varian Chem Elut cartridge followed by 50mL of ethyl acetate. The ethyl acetate solution was dried over MgSO₄ andconcentrated. This crude material was dissolved in 1 mL of methanol,purified by preparative HPLC and freeze-dried to give the TFA salt ofthe title compound.

Synthesis of Cis-4-fluorocyclohexylamine

Step 1. Synthesis ofTrans-(t-butoxy)-N-(4-hydroxycyclohexyl)-carboxamide

A suspension of trans-4-aminocyclohexanol (1 equivalent) in THF (0.1 M)was treated with (Boc)₂O (1 equivalent). The mixture was stirred at roomtemperature overnight, dissolved in chloroform, and washed with water toyield a solid that was used without further purification.

Step 2. Synthesis of Cis-(t-butoxy)-N-(4-fluorocyclohexyl)carboxamide

To a solution of (t-butoxy)-N-(4-hydroxycyclohexyl)carboxamide (1equivalent) in CH₂Cl₂ (1 M) cooled to −78° C. was added dropwise asolution of DAST (1 equivalent) in CH₂Cl₂ (0.5 M). The mixture wasstirred at −78° C. for 4 hours, and then allowed to rise to roomtemperature. The solution was poured into saturated NaHCO₃ and extractedwith chloroform, dried, and evaporated. The resulting crude product waspurified on silica gel, eluting with ethyl acetate/hexane 5:95.

Step 3. Synthesis of Cis-4-fluorocyclohexylamine

A solution of cis-(t-butoxy)-N-(4-fluorocyclohexyl)carboxamide (6.51mmol) in CH₂Cl₂ (20 mL) was treated with TFA (10 mL) at roomtemperature. The reaction mixture was stirred for 2 hours, the solventwas removed in vacuo, and the crude product was dissolved in water andwashed with chloroform. The acidic aqueous phase was cooled at 0° C. andmade basic by the addition of solid KOH. The resulting mixture wasextracted with CH₂Cl₂, dried and filtered, yielding the title compoundwhich was used without further purification and as a 0.3 M solution inCH₂Cl₂.

Synthesis of 4,4-difluorocyclohexylamine

Step 1. Synthesis of N-(4,4-difluorocyclohexyl)(t-butoxy)carboxamide

A solution of (t-butoxy)-N-(4-oxocyclohexyl)carboxamide (2.5 g, 11.7mmol) in CH₂Cl₂ (45 mL) was treated with a solution of DAST (2.63 mL,19.93 mmol) in CH₂Cl₂ (6 mL) at room temperature. EtOH (141 μl, 2.3mmol) was added, and the mixture was stirred at room temperatureovernight. The solution was poured into saturated NaHCO₃ and extractedwith chloroform, dried, and evaporated to yield a 1:1 mixture of thetitle compound and (t-butoxy)-N-(4-fluoroclyclohex-3-enyl)carboxamide.This mixture was dissolved in CH₂Cl₂ (40 mL) and MeOH (14 mL) and cooledto −78° C. Ozone was bubbled into the solution for 50 minutes until itturned green and Me₂S was added (3 equivalents). The reaction mixturewas allowed to warm to room temperature, chloroform was added and theorganic phase was washed with water, dried, and evaporated to yield thetitle compound which was used without further purification.

Step 2. Synthesis of 4,4-difluorocyclohexylamine

A solution of N-(4,4-difluorocyclohexyl)(t-butoxy)carboxamide (6.51mmol) in CH₂Cl₂ (20 mL) was treated with TFA (10 mL) at roomtemperature. The reaction mixture was stirred for 2 hours, the solventwas removed in vacuo, and the crude product was dissolved in water andwashed with chloroform. The acidic aqueous phase was cooled at 0° C. andmade basic by the addition of solid KOH. The resulting mixture wasextracted with CH₂Cl₂, dried, and filtered yielding the title compoundwhich was used without further purification as a 0.3 M solution inCH₂Cl₂.

Procedure 1 Synthesis of 6-fluoro Analog of 7-azido-quinazoline-4-one(1)

Step 1: Synthesis of(2-amino-4,5-difluorophenyl)-N-[2-(4-fluorophenyl)ethyl]-carboxamide

To a stirred solution of 4,5-difluoro anthranilic acid (2.0 g, 11.6mmol) in anhydrous THF (30 mL) was added hydroxybenzotriazole hydrate(HOBt) (1.56 g, 11.6 mmol), diisopropylethyl amine (2.01 mL, 11.6.mmol), and 4-fluorophenylethyl amine (1.52 mL, 11.6 mmol). After all ofthe HOBt had completely dissolved, EDCI (2.21 g, 11.6 mmol) was addedand the resulting orange solution was stirred at room temperature for 16hours. The solvent was removed, and the residue was chromatographed onsilica eluting with 15% EtOAc in hexanes giving the desired benzamide(2) as white crystals (3.07 g, 10.4 mmol, 90%).

Step 2: Synthesis of6,7-difluoro-3-[2-(4-fluorophenyl)ethyl]-3-hydroquinazolin-4-one

The starting benzamide (2) was dissolved in trimethyl orthoformate (20mL) and heated at 120° C. under a stream of nitrogen for 3 hours. Thesolution was cooled, and the solvent was removed by rotary evaporation.The residue was triturated with hexanes, and the solids collected byfiltration, washed with hexanes, and dried on the pump. The formamideintermediate was isolated as a white solid and confirmed by NMR. Thisintermediate was suspended in POCl₃ (10 mL) and heated to 140° C. for 3minutes. The reaction was cooled, poured over crushed ice, made slightlyalkaline with saturated sodium bicarbonate solution, and extracted withEtOAc. The organic layer was collected and dried over magnesium sulfate.Product (3) was isolated as a white solid (1.94 g, 6.38 mmol, 75% for 2steps).

Step 3: Synthesis of7-(azadiazomvinyl)-6-fluoro-3-[2-(4-fluorophenyl)ethyl]-3-hydroquinazolin-4-one

Difluoroquinazoline (3) (1.46 g, 4.6 mmol) was dissolved in DMSO (10mL), and sodium azide (3 g, 46.0 mmol) was added. The resulting mixturewas heated to 70° C. with stirring for 4 hours. The reaction wasmonitored by NMR. The reaction was cooled and diluted with water, andthe resulting precipitate collected by filtration and washed with water.The solid was dissolved in methylene chloride and dried (MgSO₄) in orderto remove trace water. Product (1) was isolated as an off-white solid(1.43 g, 4.37 mmol, 95%).

Following the formation of compound 1, final guanidine quinazolinoneswere formed following the synthetic method described below (Procedure1A):

Procedure 1A

To a solution of (1) (1 equivalent) in THF was added trimethylphosphine(1.5 equivalents), and the mixture was stirred at room temperature for10 minutes. To the iminophosphorane solution was added(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl isocyanate (1.6equivalents). The solution was heated at 70° C. overnight. To half ofthe carboimide solution was added a THF solution of(6S,2R)-2,6-dimethylpiperazine (2 equivalents). After being heated at70° C. for 2 hours, the residue was subjected to HPLC purification togive the guanidine product as its TFA salt.

The 2-fluoro-4-methoxy, 2,4-difluoro and 2,4-dichloro analogs weresynthesized via the same pathway described above. Compounds of the groupsynthesized via the pathway described above include Examples 42, 44, and45.

Example 1 Synthesis of(3R,5S)-N-(3-{2-[2-fluoro-4-(methyloxy)-phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7-yl)-3,5-dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

Step 1. Synthesis of (c):2-amino-N-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]4-nitro-benzamide

2-Fluoro-4-methoxyphenylethylamine ((a): 1 equivalent),4-nitroanthranilic acid ((b): 1 equivalent), HBTU (1.5 equivalents), anddry THF (0.5 M in (a)) were added to a dry round bottom flask. Themixture was allowed to stir for 10 hours at room temperature. Thereaction was then dry loaded onto silica gel and purified via flashchromatography using hexanes/ethyl acetate. The pure fractions werecombined and concentrated in vacuo to yield the product ((c):2-amino-N-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-nitro-benzamide) as apure solid.

Step 2. Synthesis of (d):3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-7-nitro-3H-quinazolin-4-one

The pure product ((c): 1 equivalent) of Step 1, Gold's reagent, anddioxane (0.5 M in (c)) were added to a dry round bottom flask, fittedwith a condenser, and heated to reflux for 16 hours. Once completeproduct conversion was verified by LC/MS, acetic acid (1 equivalent) andsodium acetate (1 equivalent) were added to the reaction. The subsequentmixture was heated to reflux for 3 hours. Then, the reaction wasconcentrated in vacuo, taken up in ethyl acetate, and washed with water.After the organic layer was isolated, the aqueous layer was extractedwith two more portions of ethyl acetate. The organic layers were thencombined, dried over sodium sulfate, filtered through a cotton plug, andconcentrated. The crude product mixture was purified via flashchromatography using a mixture of CH₂Cl₂/MeOH. The pure fractions werecombined and concentrated in vacuo to yield the pure product ((d):3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-7-nitro-3H-quinazolin-4-one) asa pure solid.

Step 3. Synthesis of (e):7-amino-3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-3H-quinazolin-4-one

To a solution of (d), prepared as described in Step 2, in MeOH (0.25 Min (d)) was added 10% Pd/C (0.1 equivalent). The mixture was sealed witha septum and degassed with nitrogen for 10 minutes. Hydrogen was thenbubbled through the solution for 20 minutes. Once reaction completionwas verified by LC/MS, the reaction was degassed with nitrogen for 10minutes. The mixture was filtered through Celite® and concentrated invacuo to yield the product ((e):7-amino-3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-3H-quinazolin-4-one).The product was used in the next reaction without further purification.

Step 4. Synthesis of (f):3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-7-isothiocyanato-3H-quinazolin-4-one

To a mixture of (e), prepared as described in Step 3, (1 equivalent) andNaHCO₃ (3 equivalents) in acetone (0.1 M in (e)) was added thiophosgene(3 equivalents) dropwise. The resulting slurry was stirred at roomtemperature for three hours. Once reaction completion was verified byLC/MS, the reaction was concentrated in vacuo to remove solvent andexcess thiophosgene. The mixture was then taken up in ethyl acetate andwashed with water. After the organic layer was isolated, the aqueouslayer was extracted with two more portions of ethyl acetate. The organiclayers were then combined, dried over sodium sulfate, filtered through acotton plug, and concentrated in vacuo to yield the product ((f):3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-7-isothiocyanato-3H-quinazolin-4-one).The crude product was used in the next reaction without furtherpurification.

Step 5. Synthesis of (g):1-{3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-oxo-3,4-dihydro-quinazolin-7-yl}-3-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-thiourea

To a solution of (f), prepared as described in Step 4, (1 equivalent) inTHF (0.5 M in (f)) was added (1S,2S,3S,5R)-(+)-isopinocampheylamine (1.5equivalents). The reaction was stirred at room temperature for 10 hours.The crude product mixture was then concentrated in vacuo, dissolved inmethylene chloride, and purified via flash chromatography usinghexanes/ethyl acetate. The pure fractions were combined and concentratedin vacuo to yield the pure product ((g):1-{3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-oxo-3,4-dihydro-quinazolin-7-yl}-3-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-thiourea).

Step 6. Synthesis of (h):(3R,5S)-N-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7-yl)-3,5-dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

To a solution of (g), prepared as described in Step 5, (1 equivalent) indry THF (0.1 M in (g)) in a dry round bottom flask was added1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (2equivalents). The reaction was fitted with a condenser and heated to 80°C. for 1 hour. The resulting solution was allowed to cool to roomtemperature for 20 minutes. A solution of cis-2,6-dimethylpiperazine (2equivalents; 0.5 M in CH₂Cl₂) was then added to the reaction, and theresulting mixture was stirred at room temperature for 10 minutes. Themixture was then diluted with ethyl acetate and washed with water. Afterthe organic layer was isolated, the aqueous layer was extracted with twomore portions of ethyl acetate. The organic layers were then combinedand concentrated in vacuo. The crude mixture was dissolved in DMSO andpurified via preparative HPLC using water (0.1% TFA)/acetonitrile (0.1%TFA). The pure fractions were combined and concentrated in vacuo toremove the majority of acetonitrile. Sodium carbonate (15 equivalents)was then added to the resulting aqueous solution and the slurry wasallowed to sit at room temperature for 1 hour with occasional swirling.The basic aqueous solution was then extracted with 3 separate portionsof ethyl acetate. The organic layers were combined, dried over sodiumsulfate, filtered through a cotton plug, and concentrated in vacuo toyield product (h) as a free base. The resulting solid was then dissolvedin an aqueous HCl solution (1 M; 15 equivalents) and concentrated invacuo. The resulting mixture was dissolved in a 1:1 water/acetonitrilemixture and lyophilized to yield the pure Bis-HCl salt product ((h):(3R,5S)-N-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7-yl)-3,5-dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide.

Compounds where one of R³, R⁴, and/or R⁵ is fluorine are prepared usingthe methodology described above using an appropriatelyfluorine-substituted 4-nitroanthranilic acid in place of4-nitroanthranilic acid (b) in Step 1. Steps 2-6 may then be carried outto give the final product. One skilled in the art will recognize that afluorine-substituted 4-nitroanthranilic acid may be used which includesfurther substituents to produce variously substituted compounds whereR³, R⁴, and/or R⁵ are any of the groups herein described such as, butnot limited to, fluoro, chloro, alkyl, and alkaryl.

Example 2 Synthesis of7-{[1-((5S,3R)-3,5-dimethylpiperazinyl)-2-((2S,3S,1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)(1Z)-2-azavinyl]amino}-3-[2-(2,4-dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione

Step 1. Synthesis of (c):2-amino-N-[2-(2,4-dichlorophenyl)-ethyl]4-nitro-benzamide

2,4-Dichlorophenylethylamine ((a): 1 equivalent), 4-nitroanthranilicacid ((b): 1 equivalent), HBTU (1.5 equivalents), and dry THF (0.5 M in(a)) were added to a dry round bottom flask. The mixture was allowed tostir for 10 hours at room temperature. The reaction was then dry loadedonto silica gel and purified via flash chromatography usinghexanes/ethyl acetate. The pure fractions were combined and concentratedin vacuo to yield the product ((c):2-amino-N-[2-(2,4-dichloro-phenyl)ethyl]-4-nitrobenzamide) as a puresolid.

Step 2. Synthesis of (d):3-[2-(2,4-dichlorophenyl)ethyl]-7-nitro-1,3-dihydroquinazoline-2,4-dione

To a 0.3M solution of (c), prepared as described in Step 1, (2.5 g, 7.5mmol (c)) in dioxane was added 40 mL of a 20% phosgene solution intoluene, followed by 15 mL triethylamine. After stirring for 1 hour atroom temperature, solvent was removed by rotary evaporation followed byhigh vacuum. The residue was dissolved in ethyl acetate and washed threetimes with water. After drying with sodium sulfate and rotaryevaporation, an orange-brown solid ((d):3-[2-(2,4-dichlorophenyl)ethyl]-7-nitro-1,3-dihydroquinazoline-2,4-dione)was obtained in over 90% yield.

Step 3. Synthesis of (e):7-amino-3-[2-(2,4-dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione

To a solution of (d), prepared as described in Step 2, in MeOH (0.25 Min (d)) was added 10% Pd/C (0.1 equivalents). The mixture was sealedwith a septum and degassed with nitrogen for 10 minutes. Hydrogen wasthen bubbled through the solution for 20 minutes. Once reactioncompletion was verified by LC/MS, the reaction was degassed withnitrogen for 10 minutes. The mixture was filtered through Celite® andconcentrated in vacuo to yield the product ((e))7-amino-3-[2-(2,4-dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione).The product was used in the next reaction without further purification.

Step 4. Synthesis of (f):3-[2-(2,4-dichlorophenyl)ethyl]-2,4-dioxo-1,3-dihydroquinazolin-7-isothiocyanate

To a mixture of (e), prepared as described in Step 3, (1 equivalent) andNaHCO₃ (3 equivalents) in acetone (0.1 M in (e)) was added thiophosgene(3 equivalents) dropwise. The resulting slurry was stirred at roomtemperature for three hours. Once reaction completion was verified byLC/MS, the reaction was concentrated in vacuo to remove solvent andexcess thiophosgene. The mixture was then taken up in ethyl acetate andwashed with water. After the organic layer was isolated, the aqueouslayer was extracted with two more portions of ethyl acetate. The organiclayers were then combined, dried over sodium sulfate, filtered through acotton plug, and concentrated in vacuo to yield the product ((f:3-[2-(2,4-dichlorophenyl)ethyl]-2,4-dioxo-1,3-dihydroquinazolin-7-isothiocyanate).The crude product was used in the next reaction without furtherpurification.

Step 5. Synthesis of (g):7-({[((2S,3S,1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)amino]thioxomethyl}amino)-3-[2-(2,4-dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione

To a solution of (f), prepared as described in Step 4, (1 equivalent) inTHF (0.5 M in (f)) was added (1S,2S,3S,5R)-(+)-isopinocampheylamine (1.5equivalents). The reaction was stirred at room temperature for 10 hours.The crude product mixture was then concentrated in vacuo, dissolved inmethylene chloride, and purified via flash chromatography usinghexanes/ethyl acetate. The pure fractions were combined and concentratedin vacuo to yield the pure product ((g7-({[((2S,3S,1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)amino]thioxomethyl}amino)-3-[2-(2,4-dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione).

Step 6. Synthesis of (h):7-{[1-((5S,3R)-3,5-dimethylpiperazinyl)-2-((2S,3S,1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)(1Z)-2-azavinyl]amino}-3-[2-(2,4-dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione

To a solution of (g), prepared as described in Step 5, (1 equivalent) indry THF (0.1 M in (g)) in a dry round bottom flask was added1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (2equivalents). The reaction flask was fitted with a water-cooledcondenser and heated to 80° C. for 1 hour under a nitrogen atmosphere.The resulting solution was cooled to 0° C. for 20 minutes. A solution ofcis-2,6-dimethylpiperazine (2 equivalents; 0.5 M in CH₂Cl₂) was thenadded to the reaction, and the resulting mixture was stirred at 0° C.for 10 minutes. The mixture was then diluted with ethyl acetate andwashed with water. After the organic layer was isolated, the aqueouslayer was extracted with two more portions of ethyl acetate. The organiclayers were then combined and concentrated in vacuo. The crude mixturewas dissolved in DMSO/acetonitrile and purified via preparative HPLCusing water (0.1% TFA)/acetonitrile (0.1% TFA). The pure fractions werecombined and concentrated in vacuo to remove the majority ofacetonitrile. Sodium hydroxide (10 equivalents) was then added to theresulting aqueous solution and the slurry was allowed to sit at roomtemperature for 1 hour with occasional swirling. The basic aqueoussolution was then extracted with 3 separate portions of ethyl acetate.The organic layers were combined, dried over sodium sulfate, filteredthrough a cotton plug, and concentrated in vacuo to yield product (h) asa free base. The resulting solid was then dissolved in an aqueous HClsolution (1 M; 15 equivalents) and concentrated in vacuo. The resultingmixture was dissolved in a 1:1 water/acetonitrile mixture andlyophilized to yield the pure Bis-HCl salt product ((h):7-{[1-((5S,3R)-3,5-dimethylpiperazinyl)-2-((2S,3S,1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)(1Z)-2-azavinyl]amino}-3-[2-(2,4-dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione).

Example 3 Synthesis of7-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4,4-difluorocyclohexyl)vinyl]amino}-3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-3-hydroquinazolin-4-one

Step 1. Synthesis of (b):7-({[(4,4-difluorocyclohexyl)amino]-thioxomethyl}amino)-3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-3-hydroquinazolin-4-one

To a solution of (a), prepared as (f) described in Step 4 of Example 1,(1 equivalent) in THF (0.5 M in (a)) was added4,4-difluorocyclohexylamine prepared as described above (1.5equivalents). The reaction was stirred at room temperature for 10 hours.The crude product mixture was then concentrated in vacuo, dissolved inmethylene chloride, and purified via flash chromatography usinghexanes/ethyl acetate. The pure fractions were combined and concentratedin vacuo to yield the pure product ((b):7-({[(4,4-difluorocyclohexyl)amino]-thioxomethyl}amino)-3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-3-hydroquinazolin-4-one).

Step 2. Synthesis of (c):7-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4,4-difluorocyclohexyl)vinyl]amino}-3-[2-(2-fluoro-4-methoxyphenyl)-ethyl]-3-hydroquinazolin-4-one

To a solution of (b), prepared as described in Step 1, (1 equivalent) indry THF (0.1 M in (b)) in a dry round bottom flask was added1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (2equivalents). The reaction was fitted with a condenser and heated to 80°C. for 1 hour. The resulting solution was allowed to cool to roomtemperature for 20 minutes. A solution of (S)-2-methylpiperazine (2equivalents; 0.5 M in CH₂Cl₂) was then added to the reaction, and theresulting mixture was stirred at room temperature for 10 minutes. Themixture was then diluted with ethyl acetate and washed with water. Afterthe organic layer was isolated, the aqueous layer was extracted with twomore portions of ethyl acetate. The organic layers were then combinedand concentrated in vacuo. The crude mixture was dissolved in DMSO andpurified via preparative HPLC using water (0.1% TFA)/acetonitrile (0.1%TFA). The pure fractions were combined and concentrated in vacuo toremove the majority of acetonitrile. Sodium carbonate (15 equivalents)was then added to the resulting aqueous solution and the slurry wasallowed to sit at room temperature for 1 hour with occasional swirling.The basic aqueous solution was then extracted with 3 separate portionsof ethyl acetate. The organic layers were combined, dried over sodiumsulfate, filtered through a cotton plug, and concentrated in vacuo toyield product (c) as a free base. The resulting solid was then dissolvedin an aqueous HCl solution (1 M; 15 equivalents) and concentrated invacuo. The resulting mixture was dissolved in a 1:1 water/acetonitrilemixture and lyophilized to yield the pure Bis-HCl salt product ((c):7-{[1-((3S)-3-methylpiperazinyl)(1Z)-2-aza-2-(4,4-difluorocyclohexyl)vinyl]amino}-3-[2-(2-fluoro-4-methoxyphenyl)-ethyl]-3-hydroquinazolin-4-one).

Method 1 Synthesis of3-[2-(4-fluorophenyl)ethyl]-7-nitro-2-(4-pyridyl)-3-hydroquinazolin-4-one

Pyridine 4-carboxylic acid was stirred in POCl₃ at room temperature forabout 5 minutes. To the stirred solution was then added 0.9 equivalentsof (2-amino-4-nitrophenyl)-N-[2-(4-fluorophenyl)ethyl]carboxamide. Theresulting mixture was then stirred for about 15 minutes at roomtemperature in a microwave tube, which was then heated to 165° C. in amicrowave for 10 minutes. LC/MS indicated completion of the reaction.The POCl₃ was evaporated, and the residue was dissolved in CH₂Cl₂ andwashed with saturated sodium bicarbonate solution. The combined organiclayers were dried over MgSO₄ and concentrated in vacuo andchromatographed on silica gel, eluting with a gradient of EtOAc inHexanes. The resulting product,3-[2-(4-fluorophenyl)ethyl]-7-nitro-2-(4-pyridyl)-3-hydroquinazolin-4-one,was then converted to Example 77 using the procedures described inScheme 1a.

Method 2 Synthesis of2-[2-(2-fluoro-4-methoxyphenyl)ethyl]-3-methyl-7-nitro-3-hydroquinazolin-4-one

3-(2-Fluoro-4-methoxy-phenyl)-N-methyl-propionamide was synthesizedusing an EDCI mediated coupling of3-(2-fluoro-4-methoxy-phenyl)-N-methyl-propionic acid and methylamine(2M solution in THF). The amide was then taken up in POCl₃ in amicrowave vessel and the mixture was stirred about 3 minutes. To thestirred solution was added about 1 equivalent of 4-nitroanthranilicacid. The unsealed vial was stirred for 10 minutes until there was acolor change from red to yellow. The vial was then sealed and reacted ina microwave unit at 165° C. for 600 seconds. Reaction completion waschecked with LC/MS.2-[2-(2-Fluoro-4-methoxyphenyl)ethyl]-3-methyl-7-nitro-3-hydroquinazolin-4-onewas then purified by column chromatography, eluting with EtOAc inhexanes.2-[2-(2-Fluoro-4-methoxyphenyl)ethyl]-3-methyl-7-nitro-3-hydroquinazolin-4-onewas then converted to Example 90 using the procedures described abovethrough the corresponding thiourea (Scheme 1a).

Method 3 Synthesis of3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-2-(4-methylpiperazinyl)-7-nitro-3-hydroquinazolin-4-one(B) and3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-2-[imino(4-methylpiperazinyl)-methyl]-7-nitro-3-hydroquinazolin-4-one(C)

The synthesis of nitrile A was first conducted as described in J.Heterocyclic Chem., 35, 659 (1998)). Nitrile A was heated in an excessof N-methylpiperazine to 110° C. in a microwave for 600 seconds andanalyzed by LC/MS to provide B and C. Products B and C were separated bycolumn chromatography on silica gel eluting with 10% MeOH in CH₂Cl₂.Compound B was the first to come off the column. Compounds B and C werethen respectively converted to Examples 99 and 71 using the proceduresdescribed herein.

Method 4 Synthesis of3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-7-nitro-2-(1,2,3,4-tetraazol-5-yl)-3-hydroquinazolin-4-one

Nitrile 1 shown above (0.9 g, 2.4 mmoles) was dissolved in dry DMF (5mL). Sodium azide (0.8 g, 12.2 mmoles) was added and the mixture washeated at 125° C. for 1 hour. The reaction was cooled, diluted withwater (25 mL), and filtered. The collected solid was redissolved inTHF/EtOAc 1:1 (25 mL), washed with water (25 mL), and dried over MgSO₄.Filtration and solvent removal afforded 650 mg of a brown solid. The ¹HNMR (DMSO-D6, 300 MHz) was consistent with desired product formation.The product was converted to Example 78 using the procedures describedherein.

Method 5 Synthesis of3-[2-(4-fluorophenyl)ethyl]-2-[(4-methylpiperazinyl)-methyl]-7-nitro-3-hydroquinazolin-4-one(3) Step 1 Synthesis of 2-chloro-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide(1)

To a solution of 4-fluorophenylethylamine (1.0 equivalent) in dried THFwas added Hunig's base (DIEA)(1 equivalent). The mixture was thenstirred for 3 minutes at 0° C. Thereafter, a solution ofchloroacetylchloride (1.0 equivalent) in THF was added via a syringeover a period of 7 minutes. The reaction mixture was then stirred atroom temperature for 1 hour after which time the reaction mixture wascondensed in vacuo, quenched with water, extracted with ethyl acetate(3×) and dried over Na₂SO₄. After concentration in vacuo, compound 1shown above was obtained, which was carried on further without furtherpurification. LC/MS=M+H 216.1 at 2.18 minutes.

Step 2 Synthesis of2-chloromethyl-3-[2-(4-fluoro-phenyl)-ethyl]-7-nitro-3H-quinazolin-4-one(2)

Compound 1 (1.2 equivalents) was dissolved in neat POCl₃ and allowed tostir under N₂ for 5 minutes. Solid 4-nitroanthranilic acid (1.0equivalent) was then added, and the mixture was allowed to stir at roomtemperature for 10 minutes until the color changed to yellow from red.Thereafter, the reaction mixture was refluxed at 100° C. for 2 hours,followed by removal of POCl₃ in vacuo (addition of triethylamine to therotovap condenser). The crude product so obtained was neutralized with asaturated solution of NaHCO₃, extracted with ethyl acetate (3 times),dried over Na₂SO₄, and condensed in vacuo. Purification of the crudeproduct was carried out with column chromatography in several batchesusing a gradient of EtOAc in hexanes. LC/MS=M+H 3.62 at 3.5 minutes.

Step 3 Synthesis of3-[2-(4-fluorophenyl)ethyl]-2-[(4-methylpiperazinyl)-methyl]-7-nitro-3-hydroquinazolin-4-one(3)

A solution of 2 (1 equivalent) and 4-methylpiperazine (3 equivalents) in2 mL NMP were heated at 80° C. After stirring for 18 hours, the darkbrown solution was diluted with ethyl acetate and washed twice withwater. The organic phase was then dried with sodium sulfate, filteredand concentrated in vacuo, and taken on to the next step without furtherpurification. Compound 3 was then converted to Example 69 using theprocedures described herein. This procedure yielded a dark oil, andsmall amounts of NMP may remain in the product. Formation of someanalogous compounds required the addition of three equivalents ofdiisopropyl ethyl amine. Similar chemistry was used to prepare Examples67, 70, 72, 74, 75, 79, and 81 as identified in the following tables.

Step 3a Synthesis of2-[(2,4-difluorophenoxy)methyl]-3-methyl-7-nitro-3-hydroquinazolin-4-one

2,4-Difluorophenol (2.5 equivalents) was added to2-(chloromethyl)-3-methyl-7-nitro-3-hydroquinazolin-4-one (2a) inacetone and refluxed for 8 hours. The solution was then cooled to roomtemperature, washed with saturated sodium bicarbonate, dried andfiltered over sodium sulfate and concentrated in vacuo to afford2-[(2,4-difluorophenoxy)methyl]-3-methyl-7-nitro-3-hydroquinazolin-4-onein quantitative yields. Compound 3a was then converted to Example 88using the procedures described herein. Similar chemistry was used toprepare Examples 68, 89, 92, 93, 94, 95, 96, 97, 98, and 100 asidentified in the following tables.

Method 6 Synthesis of3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-7-nitrobenzo[d]1,2,3-triazin-4-one

A mixture of benzamide (1) (3.42 mmol), water (40 mL), and concentratedHCl (12 mL) was cooled in an ice bath, and a solution of NaNO₂ (3.6mmol) in water (5 mL) was added drop wise. The mixture was stirred for 1hour, and 20 mL 10 N NaOH was added. The stirring was continued foranother hour, and the reaction was neutralized with AcOH, extracted withmethylene chloride, and dried over MgSO4. The crude product waschromatographed on silica (30%) EtOAc/hexanes) yielding the desiredproduct as a yellow solid. The purified compound was then converted toExample 102 using the procedures described herein.

Method 7 Synthesis of6-amino-2-[2-(2-fluoro-4-methoxyphenyl)ethyl]-2-hydroisoquinolin-1-one

Step 1

The diacid A (1 equivalent) was added to a flask equipped with a refluxcondenser and dean stark trap and charged with dry toluene. The mixturewas heated to reflux and then 2-(2-fluoro-4-methoxy-phenyl)-ethylamine B(1 equivalent) was added. The reaction was kept at reflux overnight, andthen the toluene was removed by rotary evaporation. Purification byflash chromatography using ethyl acetate/hexanes provided the product Cin 30% yield.Step 2

The imide (C) was dissolved in CH₂Cl₂ and cooled to −78° C. 3equivalents of DIBAL (1M in CH₂Cl₂) were added, and the reaction wasstirred at −78° C. for 1 hour when LC/MS indicated completion of thereaction. The solution was then diluted with ether and 10 equivalents ofNaF and 4 equivalents water were added. The reaction was then stirredfor an hour. The reaction was then filtered through Celite® to yield thecrude pyridone amine (D). Compound D was then converted to Example 103using the procedures described herein. Similar chemistry was used toprepare Example 104 as identified in the final table.

Example Coupling of Piperazinone with Thiourea

Synthesis of(3S)-N-{3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin-7-yl}-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide(Example 216)

A solution of thiourea (1) (1.796 g, 3.07 mmol) and6-methylpiperazin-2-one (0.525 g, 4.60 mmol) in THF (50 mL) was treatedwith PS-CDI (6.5 mmol, 5.0 g of 1.3 mmol/g resin) and heated at 80° C.for 13 hours. The reaction was filtered, and the resin was washed withTHF. The crude product was then concentrated in vacuo and purified bycolumn chromatography (0-5% 2.0 N NH₃ in MeOH/CH₂Cl₂) to provide 1.55 gof the title compound (Example 216) as a tan solid.

As noted below, the compounds in the following tables were preparedusing the methodology described herein from commercially availablestarting materials which are readily recognizable by those skilled inthe art or by using known synthetic methods. For example, Example 11 wasprepared using the methodology described in Scheme 1a and theappropriate amino indanol. Examples 14 and 18 which includehydroxymethyl-substituted arylalkyl groups were also prepared using thegeneral methodology of Scheme 1a with the appropriate amino alcohol.N-cyano substituted piperazine compound Example 36 was prepared by:first, mono-Boc protecting 2,6-trans dimethylpiperazine; second,treating the mono-Boc protected compound with cyanogen bromide (2.5equivalents) and Hunig's base (1.1 equivalent); third, purifying theresulting nitrile piperazine compound on silica gel; fourth,deprotecting the purified compound; and fifth, reacting the resultingpurified nitrile trans dimethyl piperazine compound using the methodsdescribed herein to produce Example 36. Compounds such as Examples 73and 76 were prepared using the procedure of Method 2 with theappropriated amides of methacrylic acid and acetic acid.

The compounds in the following tables were prepared using themethodology described in the above procedures, methods, and examples.The starting materials used in the syntheses are recognizable to one ofskill in the art and are commercially available or may be prepared usingknown methods. The synthesis of various guanidine compounds is known inthe art. Such synthesis information may be found in the followingreferences each of which is hereby incorporated by reference in itsentirety as if fully set forth herein: PCT publication WO 02/18327; PCTpublication WO 03/099818; U.S. patent application Ser. No. 09/945,384;U.S. patent application Ser. No. 10/444,495; U.S. Provisional PatentApplication Ser. No. 60/230,565; U.S. Provisional Patent ApplicationSer. No. 60/245,579; U.S. Provisional Application Ser. No. 60/282,847;U.S. Provisional Application Ser. No. 60/353,183; U.S. ProvisionalApplication Ser. No. 60/353,188; U.S. Provisional Application Ser. No.60/382,762; U.S. Provisional Application Ser. No. 60/441,019; U.S.Provisional Application Ser. No. 60/473,317; U.S. ProvisionalApplication Ser. No. 60/523,336; and U.S. Provisional Application Ser.No. 60/524,491.

Table of Examples 4-66 No. Structure Name MH+ 4

(3S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3-methyl-N′-[(1S,2S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 575.7 5

(3S,5S)-N-(3-{2-(2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide 589.8 6

(3R,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3,5-dimethyl-N′- [(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 589.8 7

(3S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3-methyl-N′-[4-(trifluoromethyl)cyclohexyl]- piperazine-1-carboximidamide 589.6 8

N-[2-(dimethylamino)ethyl]-N′- (3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydroquinazolin-7-yl)-N-(phenylmethyl)-N″- [(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]guanidine 653.9 9

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 545.7 10

(3S)-N-{3-[2-(2,4- difluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 563.7 11

(3S)-N-{3-[(1R,2S)-2-hydroxy- 2,3-dihydro-1H-inden-1-yl]-4-oxo-3,4-dihydroquinazolin-7- yl}-3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 555.7 12

(3S)-N′-(4,4- difluorocyclohexyl)-N-(3- {2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydroquinazolin-7-yl)-3-methylpiperazine-1- carboximidamide 557.6 13

(3S)-N′-(4-fluorocyclohexyl)- N-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydroquinazolin-7-yl)-3-methylpiperazine-1- carboximidamide 539.6 14

(3S)-N-{3-[(1S)-1- (hydroxymethyl)-3- methylbutyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 523.7 15

(3R,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3,5-dimethyl-N′-(2-methylcyclohexyl)piperazine- 1-carboximidamide 549.7 16

(3R,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3,5-dimethyl-N′-(4-methylcyclohexyl)piperazine- 1-carboximidamide 549.7 17

(3S,5S)-N-{3-[2-(2,4- difluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 577.7 18

(3R,5S)-N-{3-[(1S)-2-[2-fluoro- 4-(methyloxy)phenyl]-1-(hydroxymethyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 619.8 19

(3S,5S)-N-{3-[(1S)-2-[2-fluoro- 4-(methyloxy)phenyl]-1-(hydroxymethyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 619.8 20

(3R,5S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3,5- dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 559.7 21

(3R)-3-(dimethylamino)-N-(3- {2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]pyrrolidine-1- carboximidamide 589.822

(3S)-3-(dimethylamino)-N-(3- {2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]pyrrolidine-1- carboximidamide 589.823

(3S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-4-hydroxy-3-methyl-N′-[(1S,2S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 591.7 24

(3S,5S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3,5- dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 559.7 25

(3R,5S)-N-{3-[2-(2,4- difluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 577.7 26

(3R,5S)-N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 573.8 27

(3S,5S)-N-{3-[2-(2-fIuoro-4- methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyolo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 573.8 28

(3R,5S)-N-{3-[(1S)-2-(4- fluorophenyl)-1- (hydroxymethyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboxmidamide 589.8 29

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-4- hydroxy-3-methyl-N′- [(1S,2S,5R)-2,6,6-trimethylbioyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 561.7 30

(3R,5S)-N-{3-[2-(4- chlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3,5- dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbioyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 576.2 31

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′-[(1S,2S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 610.6 32

(3R,5S)-N-{3-[(1S)-2-(4- chlorophenyl)-1- (hydroxymethyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′-[(1S,2S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 606.2 33

(3R,5S)-N-{3-[(1S)-2-hydroxy- 1-(phenylmethyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′-[(1S,2S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 571.8 34

(3R,5S)-N-{3-[2-(4-chloro-2- fluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3,5- dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 594.2 35

(3R,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydropyrido[2,3- d]pyrimidin-7-yl)-3,5-dimethyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 590.8 36

(3S,5S)-4-cyano-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 614.8 37

(3S,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-N,3,5-trimethyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazlne-1-carboximidamide 603.8 38

(3S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-N′-[(1S,2S,3S,5R)-2-(hydroxymethyl)-6,6- dimethylbicyclo[3.1.1]hept-3-yl]-3-methylpiperazine-1- carboximidamide 591.7 39

(3S)-N-{3-[2-(4- chlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 562.2 40

(3S)-N-{3-[(1S)-2-(2,4- difluorophenyl)-1-(fluoromethyl)ethyl]-4-oxo-3,4- dihydroquinazolin-7-yl}-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 595.7 41

(3S)-N-{6-fluoro-3-[2-(4- fluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 563.7 42

(3R,5S)-N-{6-fluoro-3-[2-(4- fluorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3,5- dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 577.7 43

(3S)-N-(3-{(1R)-2-[2-fluoro-4- (methyloxy)phenyl]-1-methylethyl}-4-oxo-3,4- dihydroquinazolin-7-yl)-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 589.8 44

(3S)-N-(6-fluoro-3-{2-[2-fluoro- 4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 593.7 45

(3R,5S)-N-(6-fluoro-3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 607.8 46

(3S)-N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 559.7 47

(3R,5S)-N-(3-{(1R)-2-[2- fluoro-4-(methyloxy)phenyl]-1-methylethyl}-4-oxo-3,4- dihydroquinazolin-7-yl)-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 603.8 48

(3S,5S)-N-(3-{(1R)-2-[2- fluoro-4-(methyloxy)phenyl]-1-methylethyl}-4-oxo-3,4- dihydroquinazolin-7-yl)-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbioyolo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 603.8 49

(3S)-N-{3-[(1R)-2-(2-fluoro-4- methylphenyl)-1-methylethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 573.8 50

(3S,5S)-N-{3-[(1R)-2-(2- fluoro-4-methylphenyl)-1-methylethyl]-4-oxo-3,4- dihydroquinazolin-7-yl}-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 587.8 51

(3R,5S)-N-{3-[(1R)-2-(2,4- dichlorophenyl)-1- methylethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3,5- dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 624.7 52

(3S)-N-{3-[(1R)-2-(2,4- dichlorophenyl)-1- methylethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 610.6 53

(3S)-N-{3-[(1R)-2-(4- fluorophenyl)-1-methylethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 559.7 54

(3R,5S)-N-{3-[(1R)-2-(4- fluorophenyl)-1-methylethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3,5-dimethyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 573.8 55

(3S)-N-{3-[(1R)-2-(4- chlorophenyl)-1-methylethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 576.2 56

(3R,5S)-N-{3-[(1R)-2-(4- chlorophenyl)-1-methylethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3,5-dimethyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 590.2 57

(3R,5S)-N-{3-[(1R)-2-(4- bromophenyl)-1-methylethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3,5-dimethyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 634.7 58

(3R,5S)-N-{3-[2-(2,4- difluorophenyl)ethyl]-2,4- dioxo-1,2,3,4-tetrahydroquinazolin-7-yl}-3,5- dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 593.7 59

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-1-methyl- 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 575.7 60

(3R,5S)-N-{3-[(1S)-2-(2,4- dichlorophenyl)-1- (hydroxymethyl)ethyl]-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-7-yl}-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 656.7 61

(3S)-N-(2-hydroxy-3-methyl-4- oxo-3,4-dihydroquinazolin-7-yl)-3-methyl-N′- [(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 453.6 62

(3S)-N-[3-(2-{4-[(4- fluorophenyl)carbonyl]- piperidin-1-yl}ethyl)-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 672.9 63

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-2,4- dioxo-1,2,3,4-tetrahydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 612.6 64

(3S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-2,4- dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 591.7 65

(3R,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-7-yl)-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 605.8 66

(3S)-N′-(4,4- difluorocyclohexyl)-N-(3-{2-[2- fluoro-4-(methyloxy)phenyl]ethyl}-2,4- dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3- methylpiperazine-1- carboximidamide 573.6

Table of Examples 67-101 No. Structure Name MH+ 67

(3R,5S)-N-{3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-2-[(4-methylpiperazin-1-yl)methyl]-4- oxo-3,4-dihydroquinazolin-7-yl}-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 701.9 68

(3S)-N-{3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-2-[(methyloxy)methyl]-4-oxo-3,4- dihydroquinazolin-7-yl}-3-methyl-N′-[(1S,2S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 619.8 69

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-2-[(4-methylpiperazin-1-yl)methyl]-4- oxo-3,4-dihydroquinazolin-7-yl}-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 657.9 70

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-2-(1H-imidazol-1-ylmethyl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 625.8 71

(3S)-N-{3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-2-[imino(4-methylpiperazin-1- yl)methyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine- 1-carboximidamide 700.9 72

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-2-[(4-hydroxypiperidin-1-yl)methyl]-4- oxo-3,4-dihydroquinazolin-7-yl}-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 658.9 73

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-2-(1- methylethenyl)-4-oxo-3,4-dihydroquinazolin-7-yl]-3- methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 585.8 74

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-2-[(3-hydroxypiperidin-1-yl)methyl]- 4-oxo-3,4- dihydroquinazolin-7-yl}-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 658.9 75

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-4-oxo-2-(2H-tetrazol-2-ylmethyl)-3,4- dihydroquinazolin-7-yl]- 3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 627.8 76

(3S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-2- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)- 3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 589.8 77

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-2- pyridin-4-yl-3,4-dihydroquinazolin-7-yl}- 3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 622.8 78

(3S)-N-[3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-2-(2H-tetrazol-5-yl)-3,4- dihydroquinazolin-7-yl]-3- methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 643.8 79

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-2- (morpholin-4-ylmethyl)-4-oxo-3,4- dihydroquinazolin-7-yl]- 3-methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 644.8 80

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-2-(1H-imidazol-1-ylmethyl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3- methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 625.8 81

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-4-oxo-2-(1H-tetrazol-1-ylmethyl)-3,4- dihydroquinazolin-7-yl]-3- methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 627.8 82

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-2-phenyl-3,4-dihydroquinazolin-7- yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide621.8 83

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-2-(2- methylpropyl)-4-oxo-3,4-dihydroquinazolin-7-yl]-3-methyl- N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 601.8 84

(3S)-N-(3-[2-(4- fluorophenyl)ethyl]-2-{2-[4-(methyloxy)phenyl]ethyl}-4-oxo- 3,4-dihydroquinazolin-7-yl)-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 679.9 85

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-2-(4- methylcyclohexyl)-4-oxo-3,4-dihydroquinazolin-7-yl]-3- methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 641.9 86

(3S)-N-(2,3-bis{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7-yl)-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 727.9 87

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-4-oxo-2-(2- phenylethyl)-3,4-dihydroquinazolin-7-yl]-3-methyl- N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 649.9 88

(3S)-N-(2-{[(2,4- difluorophenyl)oxy]methyl}-3- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 580.7 89

(3S)-N-[2-({[2-fluoro-4- (methyloxy)phenyl]oxy}methyl)-3-methyl-4-oxo-3,4- dihydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 592.7 90

(3S)-N-(2-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-3- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3-methyl- N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 590.8 91

(3S)-3-methyl-N-[3-methyl-4- oxo-2-(1H-tetrazol-1-ylmethyl)-3,4-dihydroquinazolin-7-yl]-N′- [(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 520.7 92

(3S)-N-(2-{[(4- fluorophenyl)oxy]methyl}-3- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3- methyl-N′- [(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 562.7 93

(3S)-N-(2-{[(4- chlorophenyl)oxy]methyl}-3- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3- methyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine- 1-carboximidamide 579.2 94

(3R,5S)-N-(2-{[(4- fluorophenyl)oxy]methyl}-3- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3,5- dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide 576.7 95

(3R,5S)-N-(2-{[(2,4- difluorophenyl)oxy]methyl}- 3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3,5- dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine- 1-carboximidamide 594.7 96

(3R,5S)-N-[2-({[2-fluoro-4- (methyloxy)phenyl]oxy}methyl)-3-methyl-4-oxo-3,4- dihydroquinazolin-7-yl]-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 606.8 97

(3S)-N-(2-{[(2,4- dichlorophenyl)oxy]methyl}-3- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3-methyl- N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 613.6 98

(3R,5S)-N-(2-{[(2,4- dichlorophenyl)oxy]methyl}-3- methyl-4-oxo-3,4-dihydroquinazolin-7-yl)-3,5- dimethyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 627.6 99

(3S)-N-[3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-2-(4-methylpiperazin-1-yl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 673.9 100

(3S)-N-[2-({[2-fluoro-4- (methyloxy)phenyl]oxy}methyl)-4-oxo-3-(phenylmethyl)-3,4- dihydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 667.8 101

(3S)-3-methyl-N-{2-[(4- methylpiperazin-1-yl)methyl]-4-oxo-3-prop-2-enyl-3,4- dihydroquinazolin-7-yl}-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 575.8

Table of Examples 102-112 No. Structure Name MH+ 102

(3R,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-1,2,3- benzotriazin-7-yl)-3,5-dimethyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 590.8 103

(3R,5S)-N-(2-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-1-oxo-1,2-dihydroisoquinolin-6- yl)-3,5-dimethyl-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 588.8 104

(3S)-N-{2-[2-(2,4- difluorophenyl)ethyl]-1-oxo-1,2-dihydroisoquinolin-6-yl}-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 562.7105

(3S)-N-[3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-2-(1,3-thiazol-2-yl)-3,4- dihydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 658.9 106

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-4-oxo-2-(4H-1,2,4-triazol-3-yl)-3,4- dihydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 612.8 107

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-2- pyridin-3-yl-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 622.8108

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-2- pyridin-2-yl-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 622.8109

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 623.8 110

(3S)-N-[3-[2-(4- fluorophenyl)ethyl]-2-(5-methylpyrazin-2-yl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3-methyl-N′-[(1S,2S,3S,5R)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 637.8 111

(3R)-3-(fluoromethyl)-N-(3-{2- [2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide 593.7112

(3R)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7- yl)-3-(trifluoromethyl)-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 629.7

Table of Examples 113-215 No. Structure Name MH+ 113

N-{3-[2-(2-fluoro-4-methoxy- phenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- hydroxy-N′-[(1R,2S,3S,5S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept-3- yl]azetidine-1-carboximidamide 548.2 114

(2R,6S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 2,6-dimethyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]morpholine-4- carboximidamide 610.3115

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3- yl]piperidine-1-carboximidamide 608.30116

4-acetyl-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]-1,4-diazepane-1- carboximidamide637.4 117

4-benzyl-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperidine-1-carboximidamide 670.3 118

N-{3-[2-(2,4-dichlorophenyl)- ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-4- phenyl-N′-[(1R,2S,3S,5S)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 657.3 119

N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-3,4-dihydroisoquinoline- 2(1H)-carboximidamide 628.3 120

N-{3-[2-(2,4-dichlorophenyl)- ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- hydroxy-N′-[(1R,2S,3S,5S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept-3- yl]azetidine-1- carboximidamide 568.2 121

N-(2,3-Dimethyl-cyclohexyl)- N′-{3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-oxo-3,4- dihydro-quinazolin-7-yl}-3,5-dimethyl-piperazine-1- carboxamidine 563.2 122

N-(1-Cyclohexyl-ethyl)-N′-{3- [2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-oxo-3,4- dihydro-quinazolin-7-yl}-3,5-dimethyl-piperazine-1- carboxamidine 563.3 123

N-{3-[2-(2-Fluoro-4-methoxy- phenyl)-ethyl]-4-oxo-3,4-dihydro-quinazolin-7-yl}-3,5- dimethyl-N′-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)- piperazine-1-carboxamidine 589.2 124

N-(6,6-Dimethyl- bicyclo[3.1.1]hept-2- ylmethyl)-N′-{3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3,5-dimethyl-piperazine-1- carboxamidine 589.2 125

N-(1-Cyclohexyl-ethyl)-N′-{3- [2-(2-fluoro-4-methoxy-phenyl)-ethyl]-4-oxo-3,4- dihydro-quinazolin-7-yl}-3,5-dimethyl-piperazine-1- carboxamidine 563.3 126

N-{3-[2-(2-Fluoro-4-methoxy- phenyl)-ethyl]-4-oxo-3,4-dihydro-quinazolin-7-yl}-N′- indan-2-yl-3,5-dimethyl-piperazine-1-carboxamidine 569.2 127

N-{3-[2-(2-Fluoro-4-methoxy- phenyl)-ethyl]-4-oxo-3,4-dihydro-quinazolin-7-yl}-3,5- dimethyl-N′-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3- ylmethyl)-piperazine-1- carboxamidine 603.4 128

N-{3-[2-(2-Fluoro-4-methoxy- phenyl)-ethyl]-4-oxo-3,4-dihydro-quinazolin-7-yl}-3,5- dimethyl-N′-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)- piperazine-1-carboxamidine 590.3 129

(3S)-N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- isopropyl-N′-[(1R,2S,3S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3-yl]- piperazine-1-carboximidamide587.3 130

(3S)-3-benzyl-N-{3-[2-(2- fluoro-4-methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-N′-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 635.3 131

(3S)-3-tert-butyl-N-{3-[2-(2- fluoro-4-methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-N′-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 601.3 132

(2S,5S)-N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 2,5-bis[2-(methylthio)ethyl]-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 693.4 133

(3S)-N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- (1H-indol-3-ylmethyl)-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 674.4 134

(8aS)-N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)- carboximidamide 585.3 135

(3S)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- isopropyl-N′-[(1R,2S,3S,5S)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 603.3 136

(3S)-3-tert-butyl-N-{3-[2-(2- fluoro-4- methoxyphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 617.4 137

(3S)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- (1H-indol-3-ylmethyl)-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 690.4 138

(2S,5S)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 2,5-bis[2-(methylthio)ethyl]-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 709.4 139

(8aS)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]hexahydropyrrolo[1,2-a]pyrazine-2(1H)- carboximidamide 601.4 140

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(2,6-dimethylphenyl)-3,5-dimethylpiperazine-1- carboximidamide 577.2 141

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2- yl]methyl}-3- methylpiperazine-1-carboximidamide 595.1 142

(3S)-N′-[(1S)-1- cyclohexylethyl]-N-{3-(2- (2,4-dichloro-phenyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3- methylpiperazine-1-carboximidamide 571.2 (MH + 3) 143

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(2,3-dimethylcyclohexyl)-3-methylpiperazine-1- carboximidamide 570.2 (MH + 2) 144

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-(4-methyl-cyclohexyl)piperazine-1- carboximidamide 558.0 (MH + 3) 145

(3S)-N′-[1,1′-bi(cyclohexyl)-2- yl]-N-{3-[2-(2,4-dichloro-phenyl)ethyl]-4-oxo-3,4- dihydroquinazolin-7-yl}-3- methylpiperazine-1-carboximidamide 623.2 146

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-(2-methylcyclohexyl)piperazine- 1-carboximidamide 555.2 147

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-(3-methylcyclohexyl)piperazine- 1-carboximidamide 557.8 (MH + 3) 148

(3S)-N′-cyclopentyl-N-{3-[2- (2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7- yl}-3-methylpiperazine-1- carboximidamide527.2 149

(3S)-N′-cycloheptyl-N-{3-[2- (2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7- yl}-3-methylpiperazine-1- carboximidamide558.1 (MH + 3) 150

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-isopentyl-3- methylpiperazine-1-carboximidamide 532.2 (MH + 3) 151

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(1,2-dimethylpropyl)-3-methylpiperazine-1- carboximidamide 532.2 (MH + 3) 152

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(1,5-dimethylhexyl)-3-methylpiperazine-1- carboximidamide 574.2 (MH + 3) 153

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-[3-(1H-imidazol-1-yl)propyl]-3-methylpiperazine- 1-carboximidamide 567.2 154

(3R)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(1,2-dimethylpropyl)-3-methylpiperazine-1- carboximidamide 531.2 (MH + 3) 155

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3-methyl-N′-[(1S)-1-phenylethyl]piperazine-1- carboximidamide 563.8 156

(3S)-N′-[(1R)-1- cyclohexylethyl]-N-{3-[2-(2,4-dichlorophenyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3-methylpiperazine-1- carboximidamide 569.2 157

(3R)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-N′-[(1S)-1-phenylethyl]piperazine-1- carboximidamide 563.2 158

(3R,5S)-N′-cyclopentyl-N-{3- [2-(2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3,5-dimethylpiperazine-1-carboximidamide 541.1 159

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′-(4-methylcyclohexyl)piperazine- 1-carboximidamide 569.0 160

(3R,5S)-N-[(1S)-1- cyclohexylethyl]-N-{3-[2-(2,4-dichlorophenyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3,5-dimethylpiperazine-1- carboximidamide 583.1 161

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(2,3-dimethylcyclohexyl)-3,5-dimethylpiperazine-1- carboximidamide 583.1 162

(3R,5S)-N′-[1,1′- bi(cyclohexyl)-2-yl]-N-{3-[2-(2,4-dichlorophenyl)ethyl]-4- oxo-3,4-dihydroquinazolin-7-yl}-3,5-dimethylpiperazine-1- carboximidamide 637.2 163

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′-(2-methylcyclohexyl)piperazine- 1-carboximidamide 569.2 164

(3R,5S)-N′-cycloheptyl-N-{3- [2-(2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin- 7-yl}-3,5-dimethylpiperazine-1-carboximidamide 637.0 165

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-isopentyl-3,5- dimethylpiperazine-1-carboximidamide 543.0 166

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(1,5-dimethylhexyl)-3,5-dimethylpiperazine-1- carboximidamide 585.1 167

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(1,2-dimethylpropyl)-3,5-dimethylpiperazine-1- carboximidamide 543.0 168

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′-(3-morpholin-4-ylpropyl)piperazine-1- carboximidamide 600.1 169

(3R,5S)-N′-[(1R)-1- cyclohexylethyl]-N-{3-[2-(2,4-dichlorophenyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3,5-dimethylpiperazine-1- carboximidamide 583.1 170

(3R)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- N′-(2,3-dimethylcyclohexyl)-3-methylpiperazine-1- carboximidamide 569.0 171

(3R,5S)-3,5-dimethyl-N-(4- oxo-3-{2-[4-(trifluoromethyl)-phenyl]ethyl}-3,4- dihydroquinazolin-7-yl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide 607.3172

(3R,5S)-N-{3-[2-(3,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3,5-dimethyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide 607.2173

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4- (phenylmethyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 651.4174

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-[2-(4- morpholinyl)ethyl]-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 673.7175

4-(4-acetylphenyl)-N-(3-{2-[2- fluoro-4-(methyloxy)phenyl]-ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 679.5176

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-(2-pyridinyl)- N′-[(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 637.6177

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′- [(1R,2S,3S,5S)-2,6,6- trimethyl-bicyclo[3.1.1]hept-3-yl]-3,4- dihydro-2(1H)- isoquinolinecarboximidamide 607.7 178

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-(2- phenylethyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 664.8179

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′- [(1R,2S,3S,5S)-2,6,6- trimethyl-bicyclo[3.1.1]hept-3-yl]-1,4′- bipiperidine-1′- carboximidamide 642.7 180

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′- [(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-4- thiomorpholine- carboximidamide 577.6 181

ethyl [4-((Z)-[(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)amino]- {[(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)-1- piperazinyl]acetate647.3 182

N′-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N-methyl-N-(1- methyl-4-piperidinyl)-N″-[(1R,2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]guanidine 603.3183

4-(1-ethylpropyl)-N-(3-{2-[2- fluoro-4-(methyloxy)phenyl]-ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-N′-[(1R,2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3-yl]-1- piperazinecarboximidamide631.4 184

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4- (phenylmethyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperidinecarboximidamide 650.3185

N′-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N-methyl-N-[2- (4-pyridinyl)ethyl]-N″- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]guanidine 611.3 186

4-(2-chlorophenyl)-N-(3-{2-[2- fluoro-4-(methyloxy)-phenyl]ethyl}-4-oxo-3,4- dihydro-7-quinazolinyl)-N′-[(1R,2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximidamide 671.3 187

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′-[(1R,2S,5S)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-4- morpholinecarboximidamide 562.3 188

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-(2- hydroxyethyl)-N′-[(1R,2S,5S)- 2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 605.3189

(2R,6S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-2,6-dimethyl- N′-[(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-4- morpholinecarboximidamide 590.3190

ethyl 1-((Z)-[(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)amino]{[(1R, 2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]imino}methyl)-4- piperidinecarboxylate632.3 191

4-(dimethylamino)-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]-1- piperidinecarboximidamide 603.3192

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl]-4- oxo-3,4-dihydro-7-quinazolinyl)-3,5-dimethyl-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperidinecarboximidamide 588.3193

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-phenyl-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 637.3194

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′- [(1R,2S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximidamide 560.3 195

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-(4-pyridinyl)- N′-[(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 636.7196

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-[2- (methyloxy)ethyl]-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 619.3197

4-[2-(dimethylamino)ethyl]-N- (3-{2-[2-fluoro-4-(methyloxy)-phenyl]ethyl}-4-oxo-3,4- dihydro-7-quinazolinyl)-N′-[(1R,2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximidamide 632.4 198

4-[3-(dimethylamino)propyl]- N-(3-{2-[2-fluoro-4-(methyloxy)-phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′-[(1R,2S,5S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl]-1- piperazinecarboximidamide 646.4 199

1-((Z)-[(3-{2-[2-fluoro-4- methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)amino]{[(1R, 2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3-yl]imino}methyl)-3- piperidinecarboxamide 603.3 200

4-acetyl-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]hexahydro-1H-1,4-diazepine-1-carboximidamide 617.3 201

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-3-methyl-4-(4- methylphenyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 665.4202

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-(tetrahydro-2- furanylmethyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 645.4203

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-[3- (methyloxy)propyl]-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 628.4204

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-propyl-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1- piperazinecarboximidamide 603.3205

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-4-methyl-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]hexahydro- 1H-1,4-diazepine-1-carboximidamide 589.3 206

N′-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N-methyl-N-(1- methyl-3-pyrrolidinyl)-N″-[(1R,2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]guanidine 589.3207

N-[(1-ethyl-3-pyrrolidinyl)- methyl]-N′-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N″-[(1R,2S,5S)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]guanidine 603.3 208

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′-[2-(1- pyrrolidinyl)ethyl]-N″-[(1R,2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]guanidine 589.3209

N-(2-cyanoethyl)-N′-(3-{2-[2- fluoro-4-(methyloxy)phenyl]-ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-N-methyl-N″-[(1R,2S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept- 3-yl]guanidine 559.2 210

N-[3-(dimethylamino)propyl]- N′-(3-{2-[2-fluoro-4-(methyloxy)-phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N-methyl-N″- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]guanidine 591.3 211

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′-(1- methylethyl)-N″-[(1R,2S,5S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept-3- yl]guanidine 434.2 212

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-N′-(2,2,6,6- tetramethyl-4-piperidinyl)-N″-[(1R,2S,3S,5S)-2,6,6- trimethyl-bicyclo[3.1.1]hept-3- yl]guanidine 631.3213

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-3-hydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]-1- pyrrolidinecarboximidamide 562.3214

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-3-hydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]-1- piperidinecarboximidamide 576.3215

(2S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4- oxo-3,4-dihydro-7-quinazolinyl)-2- (hydroxymethyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]-1-pyrrolidine- carboximidamide 576.3

Table of Examples 216-258 Ex. Structure Name MH+ 216

(3S)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin- 7-yl}-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 666.5 217

(3S)-N-{3-[2-(4-chloro-2- fluorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3-methyl- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 671.3 218

(3S)-N-{3-[2-(4- fluorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3-methyl- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 637.4 219

(3S)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyrazin-2-yl-3,4- dihydroquinazolin-7-yl}-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 667.5 220

(3R)-3-(difluoromethyl)-N-{3-[2-(2- fluoro-4-methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4- dihydroquinazolin-7-yl}-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 688.3 221

(3S)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-2-morpholin-4-yl-4-oxo-3,4- dihydroquinazolin-7-yl}-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 674.6 222

(3S)-N-{3-[2-(4- chlorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3-methyl- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 653.5 223

(3S)-N-{2-[(3R,5S)-3,5- dimethylpiperazin-1-yl]-3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-4- oxo-3,4-dihydroquinazolin-7-yl}-3-methyl-5-oxo-N-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 701.5 224

(3S)-N-{2-(cyclopropylamino)-3-[2- (2-fluoro-4-methoxyphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}- 3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 644.5 225

(3S)-N-[3-[2-(4- chlorophenyl)ethyl]-2-(1H-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- dihydroquinazolin-7-yl]-3-methyl-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 641.4 226

(3S)-N-{3-[2-(4- bromophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3-methyl- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 699.2 227

(3R)-N-{3-[2-(4- bromophenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin- 7-yl}-3-(difluoromethyl)-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 720.1 228

(3R)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3- (difluoromethyl)-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 709.5 229

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3-methyl- 5-oxo-N′-[(1S,2S3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 687.5 230

(3S)-N-{3-[2-(4- bromophenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin- 7-yl}-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 696 231

(3R)-N-{3-[2-(4 bromophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl]-3- (difluoromethyl)-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 719.4 232

(3S)-N-{2-(cyclopropylamino)-3-[2- (2,4-dichlorophenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine-1-carboximidamide664.4 233

(3R)-N-{3-[2-(4-bromo-2- fluorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3- (difluoromethyl)-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 739.1 234

(3R)-3-(difluoromethyl)-N-{3-[2-(2- fluoro-4-methoxyphenyl)ethyl]-4-oxo-2-pyrazin-2-yl-3,4- dihydroquinazolin-7-yl}-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 689.5 235

(3R)-N-{3-[2-(4- chlorophenyl)ethyl]-4-oxo-2- pyrazin-2-yl-3,4-dihydroquinazolin-7-yl}-3- (difluoromethyl)-N′- [(1 S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 675.4 236

(3S)-N-[3-[2-(4- chlorophenyl)ethyl]-2-(1H-indol-3-yl)-4-oxo-3,4-dihydroquinazolin-7- yl]-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 690.4 237

(3S)-N-{3-[2-(4-chloro-2- fluorophenyl)ethyl]-4-oxo-2-pyridin-3-yl-34-dihydroquinazolin- 7-yl}-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 670.4 238

(3R)-3-(difluoromethyl)-N-{3-[2-(2- fluoro-4-methoxyphenyl)ethyl]-4-oxo-2-piperidin-4-yl-3,4- dihydroquinazolin-7-yl}-N-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 694.6 239

(3S)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-2-[(4-methylpiperazin-1-yl)methyl]-4- oxo-3,4-dihydroquinazolin-7-yl}-3-methyl-5-oxo-N-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 701.6 240

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]-2-[(3S)-3-hydroxypyrrolidin-1-yl]-4-oxo-3,4- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 694.3 241

(3S)-N-{3-[2-(4- chlorophenyl)ethyl]-4-oxo-2- piperidin-3-yl-3,4-dihydroquinazolin-7-yl}-3-methyl- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximdamide 676.5 242

(3S)-N-{3-[2-(4- piperidin-4-yl-3,4- dihydroquinazolin-7-yl}-3-methyl-5-oxo-N[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 658.5 243

(3R)-N-{3-[2-(4- chlorophenyl)ethyl]-4-oxo-2- piperidin-3-yl-3,4-dihydroquinazolin-7-yl}-3- (difluoromethyl)-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 680.5 244

(3S)-N-[3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-2-(4-methylpiperazin-1-yl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3-methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 687.4 245

(3S)-N-{3[2(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin- 7-yl}-4-hydroxy-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 668.5 246

(3S)-4-cyano-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin- 7-yl}-3-methyl-N-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine-1-carboximidamide677.5 247

(3S)-4-(cyanomethyl)-N-{3-[2-(2- fluoro-4-methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4- dihydroquinazolin-7-yl}-3-methyl-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 691.5 248

(3R)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin-7-yl}-3-(fluoromethyl)-N′-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 670.6 249

(3R)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyridin-3-yl-3,4-dihydroquinazolin- 7-yl}-3-(trifluoromethyl)-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 706.5 250

(3R)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyridin-4-yl-3,4-dihydroquinazolin- 7-yl}-3-(fluoromethyl)-N′-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 670.5 251

(3R)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyrazin-2-yl-3,4- dihydroquinazolin-7-yl}-3-(fluoromethyl)-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 671.4 252

(3R)-N-[3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-(4H-1,2,4-triazol-3-yl)-3,4- dihydroquinazolin-7-yl]-3-(fluoromethyl)-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 660.5 253

(3R)-N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-2-morpholin-4-yl-4-oxo-3,4- dihydroquinazolin-7-yl}-3-(fluoromethyl)-N-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 678.5 254

(3R)-N-[3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-(1,3-thiazol-2-yl)-3,4- dihydroquinazolin-7-yl]-3- (fluoromethyl)-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 676.4 255

(3R)-N-[3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-2-(1H-imidazoi-2-yl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3-(fluoromethyl)-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 659.5 256

(3R)-N-{2-cyano-3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-3,4-dihydroquinazolin-7-yl}-3- (fluoromethyl)-N′-[(1S,2S,5R)-26,6-trimethylbicyclo[3.1.1]hept- 3-yl]piperazine-1-carboximidamide618.4 257

(3R)-3-(fluoromethyl)-N-{2- (fluoromethyl)-3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4- dihydroquinazolin-7-yl}-N′- [(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 595.6 258

(3R)-N-{2-(cyclopropylamino)-3- (2-(2-fluoro-4-methoxyphenyl)ethyl]-4-oxo-3,4- dihydroquinazolin-7-yl}-3-(fluoromethyl)-N′-[(1S,2S,3S,5R)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 648.5

Table of Examples 259-343 Ex. Structure Name 259

N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]-4- oxo-3,4-dihydroquinazolin-7- yl}-3-oxo-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 260

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4- dihydroquinazolin-7-yl]-3-oxo-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 261

(3R,5S)-4-cyano-N-{3- [2-(2-fluoro-4- methylphenyl)ethyl]-4- oxo-3,4-dihydroquinazolin-7- yl}-3,5-dimethyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 262

(3S)-N-{3-[2-(2-fluoro- 4-methylphenyl)ethyl]- 4-oxo-3,4-dihydroquinazolin-7- yl}-3-methyl-5-oxo-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide 263

2-acetyl-N-{3-[2-(2- fluoro-4- methylphenyl)ethyl]-4- oxo-3,4-dihydroquinazolin-7- yl}-N′-[(1R,2S,3S,5S)- 2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]hydrazinecarboximi- damide 264

((Z)-({3-[2-(2-fluoro-4- methylphenyl)ethyl]-4- oxo-3,4-dihydroquinazolin-7- yl}amino){[(1R,2S,3S, 5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)hydra-zinecarboximidamide 265

4-(4-acetylphenyl)-N- (3-{2-[2-fluoro-4- (methyloxy)phenyl]eth-yl}-4-oxo-3,4-dihydro- 7-quinazolinyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperazinecarboximida- mide 266

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth- yl}4-oxo-3,4-dihydro-7-quinazolinyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-3,4-dihydro- 2(1H)-isoquinolinecarboximid- amide 267

N-(3-{2-[2-fluoro-4-(methyloxy) phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4- thiomorpholinecarboxi midamide 268

ethyl [4-((Z)-[(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro- quinazolinyl)amino]{[(1 R,2S,5S)-2,6,6-trimethylbicyclol3.1.1]hept-3- yl]iminolmethyl)-1- piperazinyl]acetate269

N-(3-{2-[2-fluoro-4- (methyloxy)pheny]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-4- (phenylmethyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 270

4-(2-chlorophenyl)-N- (3-{2-[2-fluoro-4- )methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro- 7-quinazolinyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperazinecarboximida mide 271

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3 4-dihydro-7-quinazolinyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4- morpholinecarboximid amide 272

(2R,6S)-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro- 7-quinazolinyl)-2,6- dimethyl-N′-[(1R,2S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-4-morpholinecarboximid amide 273

ethyl 1-((Z)-[(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro- 7-quinazolinyl)amino]{[(1 R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]imino}methyl)-4- piperidinecarboxylate274

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-3,5- dimethyl-N- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 275

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-4- 2,6,6- trimethylbicyclol3.1.1]hept-3-yl]-1-piperazinecarboximida mide 276

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′- [(1 R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 277

4-acetyl-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro- 7-quinazolinyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]hexahydro- 1H-1,4-diazepine-1-carboximidamide 278

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-3- methyl-4-(4- methylphenyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperazinecarboximida mide 279

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-3- hydroxy-N′[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- pyrrolidinecarboximida mide 280

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-3- hydroxy-N′[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 281

(2S)-N-(3-{2-[2-fluoro- (methyloxy)phenyl]eth yl]-4-oxo-3,4-dihydro-7-quinazolinyl)-2- (hydroxymethyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- pyrrolidinecarboximida mide 282

(3R,4R)-N-(3-{2-[2- fluoro-4- yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-3,4- dihydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- pyrrolidinecarboximida mide 283

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4- thiomorpholinecarboxi midamide1,1-dioxide 284

(3S,4S)-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro- 7-quinazolinyi)-3,4-dihydroxy-N′[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-pyrrolidinecarboximida mide 285

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3 4-dihydro7-quinazolinyl)-N-4H- 1,2,4-triazol-4-yl-N″- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]guanidine 286

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-hydroxyethyl)-N″- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]guanidine 287

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-N′-(2- hydroxypropyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]guanidine 288

N′-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth 7-quinazolinyl)-N-(2-hydroxyethyl)-N- methyl-N″- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]guanidine 289

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-hydroxypropyl)-N″- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]guanidine 290

N-[1-((Z)-[(3-{2-[2- fluoro-4- yl}-4-oxo-3,4-dihydro-7-quinazolinyl)amino]{[(1 R,2S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]iminolmethyl)-3- pyrrolidinyl]acetamide 291

(2R,4R)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-4- (hydroxymethyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- pyrrolidinecarboximida mide 292

(3R)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-3- (hydroxymethyl)-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- pyrrolidinecarboximida mide 293

(3R)-N-{3-[2-(2,4- dichloropheny)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-3- hydroxy-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- pyrrolidinecarboximida mide 294

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-3- hydroxy-N′- [(1R,2S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- pyrrolidinecarboximida mide 295

(3R,5S)-4-cyano-N-[3- 2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-2-(3- pyridinyl)-3,4-dihydro- 7-quinazolinyl]-3,5-dimethyl-N′- [(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 296

(3R,5S)-N-[3-{2-[2- fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-2-(3-pyridinyl)-3,4-dihydro- 7-quinazolinyl]-4- hydroxy-3,5-dimethyl-N′-[(1R,2S,3S,5S)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 297

(2R,6S)-N-[3-{2-[2- fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-2-(3-pyridinyl)-3,4-dihydro- 7-quinazolinyl]-2,6- dimethyl-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-4-morpholinecarboximid amide 298

N-[3-{2-[2-fluoro-4- methyloxy)phenyl]eth yl}-4-oxo-2-(3-pyridinyl)-3,4-dihydro- 7-quinazolinyl]-3-oxo- N′-[(1R,2S,3S,5S)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperazinecarboximida mide 299

(3R,5S)-N-[3-{2-[2- fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-2-(3-pyridinyl)-3,4-dihydro- 7-quinazolinyl]-3,5- dimethyl-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperidinecarboximida mide 300

N-[3-{2-[2-fluoro-4- (methyloxy)phenyl]eth }yl-4-oxo-2-(3-pyridinyl)-3,4-dihydro- 7-quinazolinyl]-3- hydroxy-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximida mide 301

(3R,5S)-4-cyano-N-(3- {-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro- 7-quinazolinyl]-3,5- dimethyl-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 302

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-3- hydroxy-3-methyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximida mide 303

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazolinyl)-4- hydroxy-4-methyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 304

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl}-4-oxo-3,4-dihydro-7-quinazoliny)-4- [(methyloxy)imino]-N′-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 305

N[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-morpholinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-3- hydroxy-N′[(1R,2S,3S,SS)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximida mide 306

(3S)-N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-morpholinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-3-methyl- 5-oxo-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 307

N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-morpholinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-3,5- dimethyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 308

(3S)-N-{2-(4-acetyl-1- piperazinyl)-3-[2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydro-7- quinazolinyl}-3-methyl- 5-oxo-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 309

N-{2-(4-acetyl-1- piperazinyl)-3-[2-(24- dichlorophenyl)ethyl]-4-oxo-3,4-dihydro-7- quinazolinyl}-3- hydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximida mide 310

(3S)-N{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[(3S)-3-methyl-5-oxo-1-piperazinyl]-4- oxo-3,4-dihydro-7- quinazolinyl}-3-methyl-5-oxo-N′- [(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 311

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[(3S)-3-methyl-5-oxo-1-piperazinyl]-4- oxo-3,4-dihydro-7- quinazolinyl}-3- hydroxy-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximida mide 312

(3S)-N-(3-[2-(2,4- dichlorophenyl)ethyl]- 2-(3-hydroxy-1-azetidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3-methyl- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 313

N-(3-[2-(2,4- dichlorophenyl)ethyl]- 2-(3-hydroxy-1-azetidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3- hydroxy-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximida mide 314

(3R,5S)-4-cyano-N-[3- [2-(2,4- dichlorophenyt)ethyl]-2-(4-morpholinyl)-4- oxo-3,4-dihydro-7- quinazolinyl]-3,5- dimethyl-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 315

(2R,6S)-N-[3-[2-(2,4 dichlorophenyl)ethyl]- 2-(4-morpholinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-2,6- dimethyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4- morpholinecarboximid amide 316

N-[3-[2-(2,4 dichlorophenyl)ethyl]- 2-(4-morpholinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-N- [(1S,2R,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4- morpholinecarboximid amide 317

(3S)-N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-methyl-1-piperazinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3-methyl- 5-oxo-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 318

(2R,6S)-N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-methyl-1-piperazinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-2,6-dimethyl-N′[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-4-morpholinecarboximid amide 319

(3S)-N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-hydroxy-1-piperidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3-methyl- 5-oxo-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 320

(2R,6S)-N-[3-[2-(2,4 dichlorophenyl)ethyl]- 2-(4-hydroxy-1-piperidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-2,6- dimethyl-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-4-morpholinecarboximid amide 321

N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-hydroxy-1-piperidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-4-morpholinecarboximid amide 322

N-[3-[2-(2,4- dichlorophenyl)ethyl]-2-(4-methyl-1-piperazinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3-hydroxy-N′[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximida mide 323

(3R,5S)-4-cyano-N-[3- [2-(2,4- dichlorophenyl)ethyl]2-(4-methyl-1-piperazinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3,5- dimethyl-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 324

N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-methyl-1-piperazinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-4-oxo-N-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperidinecarboximida mide 325

N-[3-[2-(2,4 dichlorophenyl)ethyl]- 2-(4-hydroxy-1-piperazinyl)-4-oxo-3,4- dyhro-7- quinazolinyl]-3- hydroxy-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximida mide 326

(3R,5S)-4-cyano-N-[3- [2-(2,4- dichlorophenyl)ethyl]- 2-(4-hydroxy-1-piperidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3,5-dimethyl-N′[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 327

(3S)-N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-ethyl-1-piperazinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3-methyl- 5-oxo-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 328

N[3[2-(2,4 dichlorophenyl)ethyl]- 2-(4-ethyl-1- piperazinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-3- hydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximida mide 329

(3R,5S)-4-cyano-N-[3- [2-(2,4- dichlorophenyl)ethyl]- 2-(4-ethyl-1-piperazinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3,5- dimethyl-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 330

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[4-(1-methylethyl)-1-piperazinyl]-4-oxo-3,4- dihydro-7- quinazolinyl]-3-methyl-N′-[(1R,2S,3S,5R)-2- methylbicyclo[3.1.1]he pt-3-yl]-5-oxo-1-piperazinecarboximida mide 331

(3S)-N-[3-[2-(2,4 dichlorophenyl)ethyl]- 2-(4,4-difluoro-1-piperidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3-methyl- 5-oxo-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 332

N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4,4-difluoro-1-piperidinyl)-4-oxo-3,4- dihydro-7- quinazolinyl]-3- hydroxy-N′-[(1R,2S,3S,5S)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximida mide 333

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[4-(hydroxymethyl)-1-piperidinyl]-4-oxo- 3,4-dihydro-7- quinazolinyl]-3-methyl- 5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 334

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[4-(hydroxymethyl)-1-piperidinyl]-4-oxo- 3,4-dihydro-7- quinazolinyl}-3- hydroxy-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-azetidinecarboximida mide 335

N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-morpholinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-4-methyl- N′-[(1R,2S,3S,5S)- 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperazinecarboximida mide 336

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]eth yl]-4-oxo-3,4-dihydro-7-quinazolinyl)-3- hydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximida mide 337

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-3- hydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximida mide 338

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-4- (phenylmethyl)-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 339

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-hydro-7-N′-[(1R,2S,3S,5S)- 2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1-piperazinecarboximida mide 340

(3R,5S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-3,5- dimethyl-N- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-1- piperidinecarboximida mide 341

(2R,6S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-2,6- dimethyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-4- morpholinecarboximid amide 342

4-acetyl-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]hexahydro- 1H-1,4-diazepine-1-carboximidamide 343

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-N′- [(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-3,4-dihydro- 2(1H)-isoquinolinecarboximid amide Ret. LC Time Ex. Method (mm) Ion 259 B 3.35M + H 559.3 260 B 3.44 M + H 595.2 261 B 2.71 M − H 596.4 262 A 2.74 M +H 574.8 263 A 2.64 M + H 534.3 264 A 2.61 M + H 534.4 265 B 3.53 M − H677.32 266 B 3.62 M − H 606.29 267 B 3.49 M − H 576.25 268 B 3.58 M + H647.29 269 B 3.88 M + H 650.40 270 B 3.83 M + H 673.29 271 B 3.54 M + H562.25 272 B 3.59 M + H 590.29 273 B 3.67 M + H 632.32 274 B 3.75 M + H588.31 275 B 3.75 M + H 637.34 276 B 3.62 M + H 560.25 277 B 3.47 M + H617.25 278 B 3.81 M + H 665.39 279 B 3.34 M + H 562.28 280 B 3.27 M + H576.30 281 B 3.31 M + H 576.35 282 B 3.33 M + H 577.82 283 B 3.62 M + H608.20 284 B 3.74 M + H 578.21 285 B 3.87 M + H 559.27 286 A 2.72 M + H536.23 287 A 2.68 M + H 549.97 288 A 2.71 M − H 548.41 289 A 2.72 M − H548.35 290 A 2.6 M − H 601.27 291 A 2.68 M + H 612.21 292 A 2.66 M + H596.22 293 A 2.66 M + H 582.22 294 A 2.66 M + H 582.22 295 A 2.76 M − H582.25 296 A 2.73 M − H 680.39 297 A 2.76 M − H 665.41 298 A 2.64 M − H650.38 299 A 2.9 M − H 663.57 300 A 2.71 M − H 623.33 301 B 3.3 M − H612.41 302 A 2.55 M − H 560.58 303 A 2.56 M − H 588.45 304 A 2.58 M − H601.42 305 E 5.03 M + H 653 306 C 3.59 M + H 694 307 C 3.73 M + H 693308 C 3.59 M + H 735 309 C 3.65 M + H 694 310 C 3.6 M + H 721 311 C 3.61M + H 680 312 C 3.59 M + H 680 313 C 3.62 M + H 639 314 A 2.81 M + H 719315 A 2.84 M + H 695 316 A 2.78 M + H 667 317 A 2.31 M + H 707 318 A2.28 M + H 708 319 A 2.74 M + H 708 320 A 2.78 M + H 709 321 A 2.78 M +H 681 322 A 2.18 M + H 666 323 A 2.14 M + H 732 324 A 2.11 M + H 692 325A 2.63 M + H 667 326 A 2.63 M + H 733 327 A 1.88 M + H 721 328 A 2.17M + H 680 329 A 1.99 M + H 746 330 A 2.14 M − H 733 331 A 2.8 M + H 728332 A 2.85 M + H 687 333 A 2.72 M + H 722 334 A 2.68 M + H 681 335 A2.41 M + H 680 336 A 3.51 M + H 548 337 A 2.7 M + H 568 338 A 3.41 M + H670 339 A 3.06 M + H 657 340 A 3.16 M + H 608 341 A 2.74 M + H 610 342 A2.54 M + H 637 343 A 3.01 M + H 628

Table of Examples 344-390 Ret. LC Time Ex. Structure Name Method (min)Ion 344

N-{3-[2-(2-fluoro-4- methylphenyl)ethyl]- 4-oxo-3,4-dihydroquinazolin-7- yl}-3-oxo-N′- [(1R,2S,3S,5S)-2,6,6- trimethyl-bicyclo[3.1.1]hept-3-yl]-3,4,6,7- tetrahydro-5H- imidazo[4,5-c]pyridine-5- carboximidamide A 2.32 M + H 582.3 345

2-((Z-{[3[2-(2,4- dichlorophenyl)ethyl]- 2-(4- isopropylpiperazin-1-yl)-4-oxo-3,4- dihydroquinazolin-7- yl]amino}{[(1R,2S, 3S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]imino}methyl) hydrazine-carboximidamide A 2.18 M + H 696.3 346

2-acetyl-N-[3-[2- (2,4-dichlorophenyl)- ethyl]-2-(4-isopropyl-piperazin-1-yl)-4- oxo-3,4-dihydro- quinazolin-7-yl}-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]hydrazine- carboximidamide A2.26 M + H 695.4 347

(1R,4S)-N-{3-[2-(2- fluoro-4- methylphenyl)ethyl]- 4-oxo-3,4-dihydroquinazolin-7- yl}-N′- [(1R,2S,3S,5S)- 2,6,6- trimethyl-bicyclo[3.1.1]hept- 3-yl]-2,5- diazabicyclo{2.2.1}heptane-2-carboximidamide A 2.13 M + H 555.4 348

(3R)-N-{3-[2-(2- fluoro-4- methylphenyl)ethyl]- 4-oxo-3,4-dihydroquinazolin-7- yl}-3- (hydroxymethyl)-5- oxo-N′- [(1R,2S,3S,5S)-2,6,6- trimethyl- bicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamideA 2.6 M + H 589.6 349

(3R)-N-{3-[2-(2- fluoro-4- methylphenyl)ethyl]- 4-oxo-3,4-dihydroquinazolin-7- yl}-3- (hydroxymethyl)-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide A 2.48M + H 575.8 350

(8aR)-N-{3-[2-(2- fluoro-4- methylphenyl)ethyl]- 4-oxo-3,4-dihydroquinazolin-7- yl}-N′- [(1R,2S,3S,5S)- 2,6,6- trimethyl-bicyclo[3.1.1]hept- 3-yl]hexahydro- pyrrolo[1,2- a]pyrazine-2(1H)-carboximidamide B 4.22 M + H 585.3 351

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-N′- (1H-imidazol-4- ylmethyl)-N″- [(1R,2S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]guanidine trifluoroacetate A 2.54M + H 592.1 352

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4- dihydro-7-quinazolinyl)-N′- [(1R,2S,5S)-2,6,6- trimethyl- bicyclo[3.1.1]hept-3-yl]-1- piperazine- carboximidamide trifluoroacetate A 2.12 M + H 561.3353

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4- dihydro-7-quinazolinyl)-N′-(2- pyridinylmethyl)-N″- [(1R,2S,5S)-2,6,6- trimethyl-bicyclo[3.1.1]hept-3- yl]guanidine trifluoroacetate A 2.73 M + H 583.2354

ethyl (3S)-1-((Z)-[(3- {2-[2-fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4- dihydro-7-quinazolinyl)amino]{[(1R,2S,5S)-2,6,6- trimethyl bicyclo[3.1.1]hept-3-yl]imino}methyl)-3- hydroxy-L-prolinate trifluoroacetate (salt) A 2.60M + H 634.4 355

(2S,3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-2- (hydroxymethyl)-3- methyl-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl bicyclo[3.1.1]hept- 3-yl]-1-pyrrolidine- carboximidamidetrifluoroacetate (salt) A 2.70 M + H 610.3 356

(2R,3S)-N-{3-[2- (2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-3- hydroxy-2- (hydroxymethyl)-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1 - pyrrolidine- carboximidamidetrifluoroacetate (salt) A 2.73 M + H 612.2 357

(2R,3S)-N-{3-[2- (2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-3- hydroxy-2-methyl-N′- [(1R,2S,5S)-2,6,6- trimethyl-bicyclo[3.1.1]hept- 3-yl]-1- pyrrolidine- carboximidamidetrifluoroacetate (salt) A 2.78 M + H 596.2 358

(3R,5S)-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-3,5- dimethyl-N′- [(1S,2R,3R,5R)-2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- piperazine-carboximidamide B 3.01 M + H 589.23 359

(3S)-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-3- methyl-N′- [(1S,2R,3R,5R)- 2,6,6- trimethyl-bicyclo[3.1.1]hept- 3-yl]-1- piperazine- carboximidamide B 3.02 M + H575.21 360

(3R,5S)-N-[3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-2-(3-pyridinyl)-3,4- dihydro-7- quinazolinyl]-3,5- dimethyl-N′-[(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1-piperazine- carboximidamide D 2.23 M + H 666.33 361

N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4- dihydro-7-quinazolinyl)-3- [(methylsulfonyl) amino]-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- azetidine- carboximidamide D 2.5M + H 625.30 362

1-((Z)-[(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)amino]{[(1R,2S,3S,5S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]imino}methyl)- 3-azetidinyl acetate D 2.57 M +H 590.33 363

3-amino-N-{3-[2-(4- fluorophenyl)ethyl]- 4-oxo-3,4-dihydro-7-quinazolinyl}-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept-3-yl]-1-azetidine- carboximidamide D 2.19 M + H 517.20 364

(4E)-N-(3-{2-[2- fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydro-7- quinazolinyl)-3- methyl-4- [(methyloxy)imino]-N′-[(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1-piperidine- carboximidamide F 1.07 M + H 617.21 365

N-{2-(4-acetyl-1- piperazinyl)-3-[2- (2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydro- 7-quinazolinyl}-4- methyl-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- piperazine- carboximidamide C3.4 M + H 721 366

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[(3S)-3-methyl-5-oxo-1-piperazinyl]-4- oxo-3,4-dihydro-7- quinazolinyl}-4- methyl-N′-[(1R,2S,3S,5S)- 2,6,6- trimethyl- bicyclo[3.1.1]hept- 3-yl]-1-piperazine- carboximidamide C 3.49 M + H 707 367

N-{2-(2- acetylhydrazino)-3- [2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydro- 7-quinazolinyl}-3- hydroxy-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- azetidine- carboximidamide A2.76 M + H 640 368

(3S)-N-{2-(2- acetylhydrazino)-3- [2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydro- 7-quinazolinyl}-3- methyl-5-oxo-N′- [(1R,2S,3S,5S)-2,6,6- trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- piperazine-carboximidamide A 2.84 M + H 681 369

2-acetyl-N-{2-(2- acetylhydrazino)-3- [2-(2,4- dichlorophenyl)ethyl]-4-oxo-3,4-dihydro- 7-quinazolinyl}-N′- [(1R,2S,3S,5S)- 2,6,6- trimethyl-bicyclo[3.1.1]hept- 3-yl]hydrazine- carboximidamide A 2.87 M + H 641 370

N-(3-[2-(2,4- dichlorophenyl)- ethyl]-2-{[2-(dimethylamino)ethyl]amino}-4-oxo-3,4- dihydro-7- quinazolinyl)-3-hydroxy-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept-3-yl]-1-azetidine- carboximidamide A 2.2 M + H 654 371

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[(2- hydroxyethyl)amino]-4-oxo-3,4-dihydro- 7-quinazolinyl}-3- hydroxy-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- azetidine- carboximidamide A2.73 M + H 627 372

(3S)-N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[(2- hydroxyethyl)amino]-4-oxo-3,4-dihydro- 7-quinazolinyl}-3- methyl-5-oxo-N′- [(1R,2S,3S,5S)-2,6,6- trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- piperazine-carboximidamide A 2.68 M + H 668 373

N²-{3-[2-(2,4- dichlorophenyl)ethyl]- 7-[([(3S)-3-methyl- 5-oxo-1-piperazinyl]{[(1R,2S, 3S,5S)-2,6,6- trimethyl- bicyclo[3.1.1]hept-3-yl]amino}methylidene)amino]- 4-oxo-3,4- dihydro-2- quinazolinyl}-N¹-methylglycinamide A 2.31 M + H 695 374

N²-{3-[2-(2,4- dichlorophenyl)ethyl]- 7-[((3-hydroxy-1-azetidinyl){[(1R,2S, 3S,5S)-2,6,6- trimethyl- bicyclo[3.1.1]hept-3-yl]amino}methyl- idene)amino]-4-oxo-3,4- dihydro-2- quinazolinyl}-N¹-methylglycinamide A 2.35 M + H 654 375

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 2-[methyl- (methyloxy)amino]-4-oxo-3,4-dihydro-7- quinazolinyl}-3- hydroxy-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]-1-azetidine- carboximidamideA 0.93 M + H 627 376

2-acetyl-N-{3-[2- (2,4-chloro- phenyl)ethyl]-2- [methyl(methyloxy)amino]-4-oxo-3,4- dihydro-7- quinazolinyl}-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]hydrazine- carboximidamide A2.31 M + H 628 377

N-[3-[2-(2,4- dichlorophenyl)ethyl]- 2-(4-ethyl-1- piperazinyl)-4-oxo-3,4-dihydro-7- quinazolinyl]-4- methyl-N′- [(1R,2S,3S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]-1- piperazine-carboximidamide trifluoroacetate. A 1.75 M + H 707 378

(3R,5S)-3,5- dimethyl-N-[4-oxo-3- (2-phenylethyl)-3,4-dihydroquinazolin-7- yl]-N′- [(1R,2S,3S,5S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide A 2.09 M + H541.26 379

2-(2,2- dimethylpropanoyl)- N-{3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-3,4- dihydroquinazolin-7- yl}-N′- [(1S,2S,3S,5R)- 2,6,6-trimethyl- bicyclo[3.1.1]hept- 3-yl]hydrazine- carboximidamide A 2.34M + H 591.00 380

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4- dihydroquinazolin-7-yl}-2-(2,2- dimethylpropanoyl)- N-[(1S,2S,3S,5R)- 2,6,6- trimethyl-bicyclo[3.1.1]hept- 3-yl]hydrazine- carboximidamide A 2.51 M + H 611.00381

(3R,5S)-N′-(4- chloro-2- methylphenyl)-N-{3- [2-(2,4-dichlorophenyl)ethyl]- 4-oxo-3,4- dihydroquinazolin-7- yl}-3,5-dimethylpiperazine- 1-carboximidamide C 3.27 M + H 599.1 382

(3R,5S)-N-{3-[2- (2,4- dichlorophenyl)ethyl]- 4-oxo-3,4-dihydroquinazolin-7- yl}-N′-(4-fluoro-2- methylphenyl)-3,5-dimethylpiperazine- 1-carboximidamide C 3.02 M + H 583.3 383

N-{3-[2-(2,4- dichlorophenyl)ethyl]- 4-oxo-3,4- dihydroquinazolin-7-yl}-N′-(2- fluorophenyl)-3- hydroxyazetidine-1- carboximidamide C 3.29M + H 530.0 384

(3S)-3-methyl-N-(11- oxo-6-phenyl- 6,8,9,11-tetrahydro- 7H-pyrido[2,1-b]quinazolin-3-yl)- N′-[(1R,2S,3S,5S)- 2,6,6- trimethyl-bicyclo[3.1.1]hept- 3-yl]piperazine-1- carboximidamide A 1.72 M + H553.3 385

(3S)-3-methyl-N-(11- oxo-6-pyridin-2-yl- 6,8,9,11-tetrahydro-7H-pyrido[2,1- b]quinazolin-3-yl)-N′- [(1R,2S,3S,5S)- 2,6,6- trimethyl-bicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide A 1.33 M + H554.3 386

(2R,6S)-2,6- dimethyl-N-(11-oxo- 6-phenyl-6,8,9,11- tetrahydro-7H-pyrido[2,1- b]quinazolin-3-yl)-N′- [(1R,2S,3S,5S)- 2,6,6- trimethyl-bicyclo[3.1.1]hept-3- yl]morpholine-4- carboximidamide A 2.22 M + H568.3 387

methyl (2S)-4-((Z)- ({2-[2-(2-fluoro-4- methoxyphenyl) ethyl]-1-oxo-3-pyridin-3-yl-1,2- dihydroisoquinolin-6- yl}amino){[(1R,2S, 3S,5S)-2,6,6-trimethyl- bicyclo[3.1.1]hept-3- yl]imino}methyl)-2- methylpiperazine-1-carboxylate A 2.24 M + H 710.4 388

(3S)-4-(4- aminobutanoyl)-N- {3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-4-oxo-2-pyridin-3- yl-3,4-dihydro- quinazolin-7- yl}-3-methyl-N′-[(1R,2S,3S,5S)- 2,6,6- trimethyl- bicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide A 1.78 M + H 737.5 389

(3S)-N-[3-[2-(2- fluoro-4- methoxyphenyl)ethyl]- 2-(6-morpholin-4-ylpyridin-3-yl)-4-oxo- 3,4-dihydro- quinazolin-7- yl]-3-methyl-5-oxo-N′-[(1R,2S,3S,5S)- 2,6,6- trimethyl- bicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide A 2.33 M + H 751.4 390

(3S)-N-{2-[6- (dimethylamino) pyridin-3-yl]-3-[2-(2- fluoro-4-methoxyphenyl)ethyl]- 4-oxo-3,4- dihydroquinazolin-7-yl}-3-methyl-5-oxo- N′-[(1R,2S,3S,5S)- 2,6,6-trimethyl-bicyclo[3.1.1]hept-3- yl]piperazine-1- carboximidamide A 2.31 M + H709.4

Table of Examples 391-396 Ex. Structure Name MW 391

(3S)-N-{3-[2-(4- chlorophenyl)ethyl]-4-oxo-2-[(2S)-pyrrolidin-2-yl]-3,4- dihydroquinazolin-7-yl}-3- methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1 ]hept-3-yl]piperazine-1-carboximidamide 644.3 392

(3S)-N-[3-[2-(4- chlorophenyl)ethyl]-2-(1-methylpiperidin-3-yl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3-methyl-5-oxo-N′- [(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1 ]hept-3-yl]piperazine-1-carboximidamide 672.3 393

(3S)-N-[3-[2-(4- chlorophenyl)ethyl]-4-oxo-2- (1H-pyrrol-2-yl)-3,4-dihydroquinazolin-7-yl]-3- methyl-5-oxo-N′- [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]piperazine-1-carboximidamide 640.2 394

(3S)-N-[3-[2-(4- chlorophenyl)ethyl]-2-(1-methyl-1H-imidazol-4-yl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3- methyl-5-oxo-N′-[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 655.2 395

(3S)-N-{2-(1- azabicyclo[2.2.2]oct-3-yl)-3-[2-(4-chlorophenyl)ethyl]-4-oxo- 3,4-dihydroquinazolin-7-yl}-3-methyl-5-oxo-N′- [(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide 684.3 396

(3S)-N-[3-[2-(4- chlorophenyl)ethyl]-2-(1-methylpiperidin-4-yl)-4-oxo-3,4- dihydroquinazolin-7-yl]-3-methyl-5-oxo-N′- [(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1-carboximidamide

HPLC Methods

HPLC Method A Semi-Polar Method

This method was accomplished by injection of 3 μL of sample onto aSynergiMax-RP (50×2.0 mm) column (4 μm particle size). Elution was with15% methanol to 100% methanol over 3.5 minutes, then 1 minute at 100%methanol. Column was heated at 50° C. and the flow rate was 1.5mL/minute. The water contained 0.1% formic acid, and the methanolcontained 0.075% formic acid by volume. DAD scans were collected from220 to 400 nm.

HPLC Method B Semi-Polar Method

This method was accomplished by injection of 3 μL of sample onto aSynergiMax-RP (50×2.0 mm) column (4 μm particle size). Elution was with15% methanol to 100% methanol over 5 minutes, then 1 minute at 100%methanol. Column was at room temperature and the flow rate was 1mL/minute. The water contained 0.1% formic acid, and the methanolcontained 0.075% formic acid by volume. DAD scans were collected from220 to 400 nm.

HPLC Method C Polar Method

This method was accomplished by injection of 3 μL of sample onto aSynergiHydro-RP (50×2.0 mm) column (4 μm particle size). Elution waswith 2% methanol to 100% methanol over 5 minutes, then 1 minute at 100%methanol. Column was at room temperature and the flow rate was 1mL/minute. The water contained 0.1% formic acid, and the methanolcontained 0.075% formic acid by volume. DAD scans were collected from220 to 400 nm.

HPLC Method D Polar Method

This method was accomplished by injection of 3 μL of sample onto aSynergiHydro-RP (50×2.0 mm) column (4 μm particle size). Elution waswith 2% methanol to 100% methanol over 3.5 minutes, then 0.5 minutes at100% methanol. Column was at room temperature and the flow rate was 1.5mL/minute. The water contained 0.1% formic acid, and the methanolcontained 0.075% formic acid by volume. DAD scans were collected from220 to 400 nm.

HPLC Method E Polar Method

This method was accomplished by injection of 3 μL of sample onto aSynergiHydro-RP (50×2.0 mm) column (4 μm particle size). Elution waswith 2% methanol to 100% methanol over 5 minutes, then 1 minute at 100%methanol. Column was at room temperature and the flow rate was 0.8mL/minute. The water contained 0.1% formic acid, and the methanolcontained 0.075% formic acid by volume. DAD scans were collected from220 to 400 nm.

HPLC Method F Standard Method

This method was accomplished by injection of 3 μL of sample onto aSynergiHydro-RP (50×2.0 mm) column (4 μm particle size). Elution waswith 10% methanol to 100% methanol over 3 minutes, then 1 minute at 100%methanol. Column was at room temperature and the flow rate was 2.0mL/minute. The water contained 0.1% formic acid, and the methanolcontained 0.075% formic acid by volume. DAD scans were collected from220 to 400 nm.

EC₅₀ values of test compounds were determined by treating cellsexpressing MC4-R with test compound and lysing the cells and measuringintercellular cAMP concentration with an Amersham-Pharmacia RPA-559 cAMPScintillation Proximity Assay (SPA) kit. EC₅₀ values of test compoundswere also determined using the following method reported by Goetz, etal. which is hereby incorporated by reference in its entirety and forall purposes as if fully set forth herein. Goetz, A. G.; Andrews J. L.;Littleton, T. R.; Ignar, D. M. DEVELOPMENT OF A FACILE METHOD FOR HIGHTHROUGHPUT SCREENING WITH REPORTER GENE ASSAYS J. Biomolec. Screening,5, pp. 377-384 (2000). CHO-6xCRE-luc+reporter cell lines expressinghuman MC1R, MC3R, MC4R, and MC5R (GenBank accession numbers X65634,LO6155, S77415 and U08353) and the CHO host reporter gene cell line werepropagated in complete medium in T225 flasks. Forty-eight hours prior toassay, cells were harvested with 2 mL of 0.05% trypsin, washed withcomplete medium and plated at a concentration of 4000 cells/well incomplete medium. Sixteen hours prior to the assay, the medium wasremoved from the cells and replaced with 90 μL/well of serum-freeDMEM/F12. At the time of the assay, agonists were added in a 10 μLvolume and plates were incubated for 4 hours at 37° C. in a cell cultureincubator. The medium was aspirated followed by the addition of 50 μL ofa 1:1 mixture of LucLite™ and dPBS containing 1 mM CaCl₂ and 1 mM MgCl₂.The plates were then sealed and subjected to dark adaptation at roomtemperature for 10 minutes before luciferase activity was quantitatedusing a TopCount™ microplate scintillation counter (Packard) using 3second/well count time. The NDP-αMSH concentration-response curve datawere expressed as a percentage of the fold stimulation in the NDP-αMSHcontrol for each receptor subtype. The control value is the average ofduplicate wells treated with 1×10⁻⁷ M NDP-αMSH.

The compounds described above were synthesized and tested according tothe assay procedures described above. Each of the Examples exhibited−log EC₅₀ values above about 3. For this reason, each of the exemplarycompounds is individually preferred and is preferred as a group.Nomenclature for these compounds was provided using ACD Name version5.07 software (Nov. 14, 2001) available from Advanced ChemistryDevelopment, Inc and Cheminnovation NamExpert+Nomenclator™ brandsoftware available from Cheminnovation Software, Inc. Some of thestarting materials were named using standard IUPAC nomenclature. TheExample compounds are illustrative and should not be construed aslimiting the instant invention in any manner.

In Vivo Studies of MC4-R Agonists on Energy Intake, Body Weight,Hyperinsulinemia, and Glucose Levels

In vivo studies are conducted to observe the effect of MCR-4 agonists onenergy intake, body weight, hyperinsulinemia, and glucose levels. Allstudies are conducted with male 9-10 week old ob/ob mice which displayearly onset of obesity, insulin resistance and diabetes due to leptindeficiency. Mice are acclimated in the facility for 1 week beforestudies and are caged individually. Vehicle-treated (control) and drugtreated mice studies are always run in parallel. In multi-day studies,mice (8-15 per group) are monitored for baseline body weight, fastinglevels of glucose, insulin, blood lipids and energy expenditure and theninjected twice daily (9 a.m. and 5 p.m.) with 3 mg/kg of a MC4-R agonistof the present invention for 4 weeks. Body weight as well as food andwater intake are monitored daily. Animals are fasted overnight formeasurements of fasting levels of glucose, insulin, and lipids once aweek until the end of the study. Energy expenditure (resting metabolicrate, i.e., O₂ consumption and CO₂ production) are monitored in airtight chambers at the end of the study on fed animals. O₂ consumptionand CO₂ production are measured using Oxymax systems (ColumbusInstruments). Oral glucose tolerance test (OGTT—a routine test fordiabetes and glucose intolerance) is performed on overnight fasted miceat the end of the study. Blood glucose and oral glucose tolerance aremeasured using a glucose monitor (Onetouch sold by Lifescan). Free fattyacids are measured using an non-esterified free fatty acids enzymaticassay (Waco Chemicals). Serum insulin levels are measured by immunoassay(Alpco).

Results

The effect of the compounds of the present invention on food intake isdetermined by measuring grams/mouse/day throughout a 4 week study. Foodis monitored every morning. Cumulative food intake represents the totalamount of grams the mice consume during the study. A significantreduction in food intake is demonstrated in those mice treated IP withthe compounds of the present invention.

The effect of the compounds of the present invention on body weight isdetermined by measuring grams/mouse throughout a 4 week study. Mice areweighed every morning. A significant body weight reduction isdemonstrated in those mice treated IP with the compounds of the presentinvention.

The effect of the compounds of the present invention on blood glucoselevels is determined by measuring blood glucose levels as represented asmg of glucose/dL of blood. Mice are fasted overnight and glucose levelsare measured the following morning. Vehicle treated mice show anincrease in blood glucose consistent with the rapid progression ofdiabetes in this mouse strain whereas, diabetes is slowed downconsiderably in drug treated mice. A significant reduction in fastingglucose levels is demonstrated in those mice treated IP with thecompounds of this invention.

The effect of the compounds of the present invention on glucose levelsduring oral glucose tolerance test (OGTT) is determined by measuringblood glucose in overnight fasted mice. Blood glucose is represented asmg of glucose/dL of blood. Glucose levels are measured the followingmorning. Orally administered glucose quickly elevates blood glucose,similar to a meal, and the response to this exogenous glucose gives ameasure of how well the body regulated glucose homeostasis. Vehicletreated mice show an elevated response to glucose consistent with theirdiabetic state, whereas drug treated mice show a very much improvedglucose disposal.

The effect of the compounds of the present invention on free fatty acid(FFA) levels is determined by measuring mmoles of FFA/L of serum. Miceare fasted overnight and free fatty acid levels are measured thefollowing morning. Vehicle treated mice show elevated levels of FFAthroughout the study consistent with their obese state, whereas the drugtreated mice diabetes show a dramatic decrease.

The effect of the compounds of the present invention on serum insulinlevels is determined by measuring serum insulin levels one hour aftersingle IP dosing of 1 and 3 mg/kg in overnight fasted ob/ob mice. Seruminsulin levels are represented as ng of insulin/mL of serum. Drugtreated mice show a dose dependent decrease relative to vehicle.

Determination of t_(1/2), C_(max), FI, Bioavailability, Cl, V_(ss), andNocturnal Efficacy

In vivo studies were conducted to observe the effect of the compounds ofthe invention in the subject animal. Male CD-1 mice, body weight of 20grams at arrival, were used in these studies. Mice were given 30 mg/kgof compound in HPMC/Tween solution or suspension via oral gavage.Plasma, brain, and liver samples were collected at time periods of 1, 2,4, 8, and 24 hours post dosing. One mouse was used per time point. Thus,a total of 5 mice were used for each compound tested. For samplecollection, mice were euthanized with CO₂. Blood samples were taken bycardiac puncture and kept on ice. Brain and liver samples were collectedimmediately after bleeding and the samples were kept on dry ice. Forcalculation of tissue half-lives (t_(1/2)s), the terminal rate constantk was estimated by the absolute value of the slope of a log-linearregression of the terminal phase of the tissue concentration-timeprofile. The tissue half-life t_(1/2) is ln(2)/k.

Male C57BL/6J mice of 6-9 weeks age were used in these studies. The micewere singly housed at least 5 days prior to the study. Two and a halfhours before the onset of the dark cycle, food was removed from the cagetop. Mice were dosed with a compound of the invention (in HPMC/Tween, asvehicle) or vehicle via oral gavage two hours before the onset of thedark cycle. Immediately before the onset of the dark cycle, pre-weighedfood was given to each mouse. Food was weighed at 16 and 24 hours afterthe introduction of food to obtain cumulative food intake values. Micewere then euthanized with CO₂ followed by cervical dislocation.

The following table includes t_(1/2) data for plasma, brain, kidney, andliver obtained after oral administration.

Tissue Half-Life Data for Various Quinazolinone Compounds (PO)Half-Lives (h) Example Plasma Brain Liver Kidney 216 1.9 14   2.1 2.7218 2.2 — 3.9 — 220 2.1 3.1 2.5 — 221 2.9 6.9 2.9 — 222 1.1 8.0 2.7 —224 3.0 10   3.1 — 227 3.9 — 9.4 — 228 — — 9.1 — 229 9.0 13   16   — 2303.1 — 5.9 — 231 2.6 15   4.6 — 233 6.4 15   44   — 234 3.5 2.6 4.9 — 2354.7 6.1 5.6 — 236 7.7 — 4.2 — 239 4.5 3.6 — — 241 21   51   17   — 2452.2 3.1 5.2 1.7 246 5.7 5.8 18   3.1 247 18   12   8.0 11   248 5.3 14  6.2 11   250 26   3.0 8.8 5.7 251 4.0 5.4 6.8 8.6 252 — — 16   8.4 2537.3 27   6.9 14   254 15   11   20   9.6 255 5.6 25   7.3 — 256 5.4 15  4.3 — 257 20   12   3.0 — 258 5.3 — 2.9 — 260 7.2 — — 7.3 274 2.1 — 2.32.7 281 5.3 — — 6.5 288 1.1 — 1.2 — 295 3.3 4.9 9.5 — 296 4.9 — 3.2 3.3301 2.5 — 3.6 9.4 337 18.9  — 4.6 5.1

All references cited herein are hereby incorporated by reference intheir entirety and for all purposes as if fully set forth herein.

It is understood that the invention is not limited to the embodimentsset forth herein for illustration, but embraces all such forms thereforeas come within the scope of the following claims.

1. A compound of formula IA, IB, or mixtures thereof, orpharmaceutically acceptable salts of the compound,

wherein R¹ is selected from substituted or unsubstituted arylalkyl,heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups;R² is selected from H or substituted or unsubstituted arylalkyl,heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl,heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl,alkynyl, or alkyl groups; R³, R⁴, and R⁵ are independently selected fromH, Cl, I, F, Br, OH, NH₂, CN, NO₂, or substituted or unsubstitutedalkoxy or alkyl groups; R^(3′) is selected from H or substituted orunsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, orcycloalkylalkyl groups; and Z is selected from a piperazinone of formula

which may be additionally substituted.
 2. The compound of claim 1,wherein R³, R⁴, and R⁵ are all H.
 3. The compound of claim 1, whereinR^(3′) is a substituted or unsubstituted polycyclic cycloalkyl group. 4.The compound of claim 3, wherein R^(3′) is a substituted orunsubstituted polycyclic cycloalkyl group of formula II


5. The compound of claim 1, wherein R¹ is a substituted or unsubstitutedarylalkyl group.
 6. The compound of claim 5, wherein R¹ is a substitutedphenylethyl group.
 7. The compound of claim 6, wherein R¹ is a4-substituted phenylethyl group or is a 2,4-disubstituted phenylethylgroup.
 8. The compound of claim 5, wherein R¹ is selected from2-fluoro-4-methoxyphenylethyl, 2-chloro-4-methoxyphenylethyl,4-fluorophenylethyl, 4-chlorophenylethyl, 4-chloro-2-fluorophenylethyl,2,4-dichlorophenylethyl, 4-bromophenylethyl, or4-bromo-2-fluorophenylethyl groups.
 9. The compound of claim 1, whereinR¹ is selected from phenylethyl, 2,4-dichlorophenylethyl,4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl,4-methylphenylethyl, 4-chlorophenylethyl, 4-fluorophenylethyl,4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl,2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl,3-fluorophenylethyl, thienylethyl, indolylethyl, 4-hydroxyphenylethyl,3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl,2-fluoro-4-methylphenylethyl, 4-chloro-2-fluorophenylethyl,4-bromo-2-fluorophenylethyl, 2-fluoro-4-methoxyphenylethyl,2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl,2,4-dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2-pyridyl)ethyl,(3-pyridyl)ethyl, (4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, or(phenyl)(hydroxymethyl)ethyl groups.
 10. The compound of claim 1,wherein R² is selected from substituted or unsubstituted heterocyclylgroups, or substituted or unsubstituted heteroaryl groups.
 11. Thecompound of claim 10, wherein R² is selected from substituted orunsubstituted pyridinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl,thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl,indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl groups. 12.The compound of claim 1, wherein R² is selected from heteroaryl orheterocyclyl groups of formula

which may be additionally substituted or may be unsubstituted.
 13. Thecompound of claim 1, wherein R² is selected from aryl or cycloalkylgroups of formula

which may be additionally substituted or may be unsubstituted.
 14. Thecompound of claim 1, wherein Z is a piperazinone of formula


15. The compound of claim 14, wherein Z is a piperazinone of formula


16. A pharmaceutical formulation comprising a pharmaceuticallyacceptable carrier and the compound of claim
 1. 17. A method of treatingan MC4-R mediated disease, comprising administering to a subject in needthereof, the compound of claim
 1. 18. The method according to claim 17,wherein the disease is obesity or type II diabetes.
 19. The methodaccording to claim 17, wherein the compound exhibits a t_(1/2) value ofless than 35 hours in a tissue with high blood perfusion.
 20. The methodaccording to claim 19, wherein the tissue with high blood perfusion isselected from a brain, a liver, a kidney or a heart.